CA1085295A - Dosage form - Google Patents

Abstract

NOVEL DOSAGE FORM
Abstract of the Disclosure Pharmaceutical dosage forms comprising an edible web having deposited thereon or at least partially thereon a particulate medicament, the webs being thereafter fabricated and finished to pharmaceutically elegant solid dosage forms having no medicament exposed on an exterior surface.
The dosage forms have a consistency of release of medicament which can be controlled to exacting specifications. The disclosed solid dosage forms are prepared by high speed automated equipment and the process by which they are made is characterized by non-destructive quality control analysis and performance evaluation both conducted on-line and integrated into the manufacturing operation. Included in the scope of the disclosed invention are certain apparatus and methods of manufacture.

Description

16 Background of the Invention 18 The orally administered solid unit do~age forms heretoforc recognizcd 1~ in the pharmaceutical industry are generally divisible into two basic forms, i.e. tablets and capsules. There are various broad categories of ~oth tnblets 21 and capsules recognized in the art such as, for ex~mple, thosc which are //~f~5f'/r~4 1 22 enteric coated to rel~ase medication in the ~tract, those which, by 23 vurious mcchanisms, rel~ase medication over an extendcd pcriod of timc, 24 cffervescents and the like. By and large such conventionul solid oral dosn~e forms suffer from a number of disadvant~igeY.

27 ~irst, convcntional ~,olid oral unit dosage forms nrc disudvnntngc-28 ou8 in that each contains, admixcd wilh the activc ingIc(licllt. n plurnlity ~ .

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of various ~ubstance~ which are tcrmed "therapeuticnlly inert or non-toxic, .~ pharm6ceuticll1 adjunct m~terials". Such materials fall under the art-3 recognized categories of diluents, excipients, binders, lubricant6, dis-integrant~, sSabilizers, buffers, preservatives and the like. Although the6e S materisls sre recognized ~18 indispensible in the art of phnrmaceutical compound-6 ing, their use nonetheles~ presents proplems which must be dealt with from a viewpoint of cost, final size und weight of the dosage unit and the like.
8 Addition~lly, each ~uch adjunct material must be evaluated before use in terms of 9 potential incompatibilities with the medicaments present. Further, certain of these materials, e.g. lubricants, may pre6ent problems concerning the bio-11 availability of the active ingredient. Also, the presence of such materials 12 must be considered in analytical procedures utilized to test for potency 13 etc. of the finished dosage form.

A second primary di~advantage in solid or~l unit dosage forms known 16 to the art i8 that the methods available for 8~i6ay thereof involve destruction 17 of the dosage form thereby permitting the te6ting of only 8 small percentage of 18 ~uch forms actually produced. Therefore, it is recognized in the art that there 19 can be considerable deviation within a given batch of 6uch do6age form~ since the mean of dosage, performance, etc. for each batch deviation i8 determined 21 by analy6is of a relatively minor number of samples.

23 The b~tch concept in itself i3 a dis~dvantage to prior art or~l solid 24 dosage forms simply from the viewpoint of the economics of the batch designation, control and evaluAtion.

P7 ¦¦ accordsnce with the present tnvention, 601id dosage units .' ll -2-,, ~ , , I, -~, primarily for oral ingestion are prov~dcd which are producib]c in lorge

2 number~ At hlgh speed and, becau~e they are prepared by a method un~que ~1 in the pharmaceutical industry, they do not suffer from the above enumerated 4 disadvantag~s of currently available solid oral dosage forms, i.e. tablets and cap~ule~. This method i~ highly advantageous in that it: eliminates 6 the necessity for b~tch requirements aE; they are conventionally recognized;
7 provide~ for continuous on-line analysis for potency as well ~s on-line per-8 formance evaluation of the dosage forms a6 they ~re being produced; pro-9 vides the substantial elimination of the necessity of mixing conventional pharmaceutical adjunct materials with the medicaments with the exception 11 of glidant~ which may be required to facilitate the flow of powders and/or 12 certain other materials advantageous for E~roduct performance; and providec 13 pharmaceutieally elegqnt unit do~age form6 which can be engineered to release 14 medicament at any desired rate and which ~re capable of a rQte of release faster than commercial tablets snd capsules presently available. In summsry, the 16 dosage form~ of the invention provide a~surance that a lsrger percent of a more 17 accurately measured amolmt of medication will be available in a more pre-18 cisely controlled time after ingestion than is the case with present commercial 19 units .
' 21 The oral unit dosage form~ of the present invention are advantageous 22 in a number of important re6pects, foremost of which i8 the fact that they 2~ are ~ubstanti~lly qualified by on-line procedure~ during high-speed, ~ub-24 stantially automated manufacturing operations. In addition, the dosage forms of the present invention are also advantageous in that the medicament con-26 tained therein is released for absorption with exceptional uniformity over a 27 ~ rge numb f doRage unito. Purther, the dosllge unit~ or the invenUon Il _3_ : - , .
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cun be en~ineercd to relea~e medicntion within u shorter period of time 2 after ingcstion than iB possible with solid oral dosage forms, e.g., tablets and

3 capsules, presently available. Therefore, the do~age unlts of the in~ention pro

4 vide superior consistency both in content of medic~ment and release thereof S for absorption.

7 Reg8rding the prior art, the following publicutions, which are directed 8 to ~olid dosage forms distinguishable from conventional tablets are noteworthy. Russell, U.S. Patent 3,444,85B issued M~y 20, 1969 describes a vehicle for the buccal admini~tration of medicaments compri6ing a strip of 11 gelatinous material containing medication, ~aid strip being divided into section 12 each of which is connected to the next by easily teHrable ligaments. In use, 13 a ~ection i8 merely separated from the strip and placed in the mouth.
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A second publication warranting mention is an article in the New England 16 Journal of Medicine, Vol. 289, No. 10 pp. 533-5 (1973). This article describes 17 a means whereby birth control medication is being made available to women in 18 the Peoples Republic of China on a very large scale. In this method, a sheet la of colored, water-soluble, curboxymethylcellulose paper is treated with a 601ution of progeststional and estrogenic materials. The shset is then per-2l forated and cut into strip~. The medicament is packaged as a 6trip of 2a 22 "squares" which are torn from the strip and taken daily. This method does not 23 provide for the concealment of the drug in the final dosage form, thereby suffer-24 ing from the disadvantuge of potential contnmination and/or inactivation of the medication once the package i8 opened. Further, by virtue of not being ~6 completely unitized, such perforated strips can give rise to uneven tearing 27 at the per!Eorations and potentislly, disproportlonant dosage .

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~8S2~5 ',''' Finally to be considered is Higuchi et al. United States Patent 3,625,214 issued December 7, 1971 which describes a dosage form utilized for controlled, i.e. sustained release of medicaments. The dosage form is comprised, in essence of a medicament containing matrix which is coated on a substrate which is then spiral wound to a final "jelly roll" appearance.
After ingestion, the medicament is released by the gradual erosion of the outer layers of substrate and also by diffusion from the sides where there is exposed medicament. There is no disclosure of whether the disclosed dosage forms are amenable to high capacity pharmaceutical manufacturing. There is further no disclosure of means whereby the disclosed dosage forms can be rendered into pharmaceutically elegant finished products.
In distinct contrast to the teachings of the foregoing publications, ~
the novel solid dosage units of the present invention are completely unitized, ~ ;
amenable to non destructive, on-line analytical testing during high capacity pharmaceutical manufacturing operations, are essentially free from pharmaceuti-cal adjunct materials that may interfere with performance, have no exposed medicament and have a superior consistency of release of medicament which enhances the efficacy thereof.
Accordingly, one aspect of the invention provides a solid pharma-ceutical unit dosage form comprising a plurality of layers of an edible,therapeutically inert web of a polymeric or paper type, at least one of said layers having a composition comprising one or more medicaments uniformly loaded in finely particulate form to one or more surfaces, said layers of web being arranged so as to have substantially no medicament loaded to an outer surface thereof, said layered arrangement of web being sealed so as to completely internalize said medicament.
Another aspect of the invention provides a method of preparing solid pharmaceutical unit dosage forms comprising uniformly loading one or more medicaments in finely particulate form to a therapeutically inert, edible web of a polymeric or paper type, fabricating a single sheet of said loaded web into a solid geometric form of predetermined shape having said medicament substantially internalized, said form being divisible into a C~ ~
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35Z~5 , , plurality of unit dosage forms, unitizing said geometric form into said plurality of unit dosage forms and sealing said unit dosage forms to complete~
ly internalize said medicament, said proceclures including at least one non-destructive testing operation to assure uniform quality of said unit dosage forms.
Thus, the unit dosage forms are prepared by high capacity pharma- ;~
; ceutical manufacturing techniques utilizing, in certain instances, novel appara-tus. As mentioned, the manufacturing process -5a-...,~ ~

l3S295 includes means to non-de6tructively test the dosage forms on-line .~ to determine the amount of medicament which has been loaded to the web prior 3 to the fabricatien thereby assaying the potency of the finished dossge units by 4 physical parameters.
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6 Deta_led Description of the Invention 8 The present invention is directed to solid, unit dosnge forms primarily for oral ingestion which are advantageous in a number of particulars over present ~olid oral dosage forms, i.e. tablets and capsules. First, the fact 11 that the dosage units of the invention are 6ubstantially free of conventional 12 pharmaceutical adjunct materials results in a ~avings in cost of raw material~
13 and manufacturing procedures as well as eliminating potential incompati-14 bilities caused by the presence of such materials. The distinction must be made here between the webs of the invention which can be con~idered adjunct ~6 material and the material~ such as fillers, binders and the lil~e which are ~dmiaLed 17 with the medicament in conventional solid dosage forms.

1~ Second, because the solid unit dosage forms of the invention are prepared continuously and subjected to on-line, non-destructive analytical 21 procedures, the requirement for batch lot manufacturing as it is known today 22 is eliminated thereby realizing a considerable economic saving and a sub-23 stantially improved level of quality control sriewed in terms of the finished dosage 24 units. The fact that the manufacturing operation of the invcntion includes means to feed back informatioll from a testing station to the manufacturin~
26 procedures immediately preceeding it thus affording on-line corrections and 27 ¦ odjustmen . Such mesns focilitl-te the removsl of onty o smotl number of Il. .. .... .... ... .. . .

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dosage units from any number desi~nated as a manuracturing lot, i.e. from the 2 positive reading immediately preceding ~ negative reading to the next following 3 positive reading. The designation and removal of æuch small quantities 4 of dosage forms thus svoids "poisoning of the barrel" and realizes both a large economic advantage over present pharmaceutical manufacturirlg procedures and a superior level of quality control parlticularly in terms of the active ingredient 7 content in the finished do~age forms. In normal operntion, the dosage form of 8 the invention are manufactured by time lot procedures, i.e. a "lot" of dosage 9 forms constitute~ the number prepared between two given points in time. This concept is believed to be unique in the pharmaceutical industry. It will be 11 appreciated, however, that some destructive testing will be required in any 12 pharmaceutical manufacturing procedure a6 a check of performance of the 1~ finished product. Such testing is, however, required to a materially smaller 14 ¦I degree in the procedures of the ~ubject invention than in conventional manu-~5 ¦I facturing operations. More important, however, i8 the fact that such destructive 16 i procedures, i.e. performance evaluation are carried out on-line with the inform-1, ation feed back thus realizing the benefits discusæed ~bove regarding the non-18 destructive procedures.
:' Third, the solid oral dosage units of the present invention are unique in 21 that they differ from conventional tablets and capsules in appearance, shape, 22 texture, etc. and therefore have the advantage of being easily identified. Also, a3 the on-line non-destructive testing procedures and continuous manufacturin~
24 operations of the pre6ent invention facilitate packaging of the unit dosage forms of the present invention on-line into individual container6 such as, for example, 26 clear plastic ~lrips of blister packages thereby saving c06ts in handling and 27 equipment .

Il -7-10~5295 Fourth, the exactneas of the preparution of a solid dosllge forms :~ of the present invention, i.e. the uniformity of deposition of the medicament on 3 the web and the precision in shaping of the final units combined with the desirabl 4 characteristics of the web itself enable the finished dosage forms to easily meet stringent specifications, of size, shape, release of medicament and the like.
6 The dosage forms of the invention also possess excellent stability and are 7 amenable to the incorporation of medicaments which are recognized as being8 adversely affected by moisture since, in certain embodiments of the present 9 invention, the medicament is deposited or loaded to the web by electrostatic deposition thereby providing an almost total absence of moisture which might 11 ~ cau~e an adverse reaction to take place. Also, wherein the dosage forms of 12 the present invention are fsbricsted from a laminate of ~heets of web, 13 medicaments recognized in the art of pharmaceutical compounding as being 1~ chemically incompatible can be deposited upon alternate sheets of web. This ~5 effectively stabilizes ~uch combination without the need to resort to such economi-16 cally unattracffve measures as the coating of one or more of such incompatible 17 substances with an insulating material, the admixture of stabilizing adjunct 18 materials with such medicaments, the incorporation of such medicaments into 19 separate tablet layers which are then pressed together and the like. Becsuse ~ ~oroc~ res ;1 ~, 20 of either or both of these~, i.e. the deposition of a medicament on the 21 web electrostatically as a dry powder and the placing of potentially incompatible 22 medicaments alternately between sheets of a laminate, the dosage forms of the 2~ invention are advantugeously useful in the administration of effervescent 24 formulations .
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26 The solid oral dosage formR of the prcsent invention are further unique 27 in that the medicament contained therein is completely internalized within the 11 , , 11 1~185Z~5 dosage form yet, in moF.t instuances, there is no couting pcr 6e applied to .~ ~hc rinished do~a~e form. This reprcsents an additional economic odv~lntngc ~or 3 the dosage forms of the subjcct invention over conventional tablets which must 4 be coated to obtain internalization of the medicament.

6 Wh;le the dosage forms prepared in accordunce with the methods of the 7 present invention are intended primarily for oral administration, dosage forms 8 suitable for rectal and/or vaginal administration are likewise contemplated.
9 Modifications in the size of the web as well as the fabricat~on methods to be described hereinafter to produce dosage forms of the desired size and shape ~i -11 will be readily apparent to those skilled in the art. Certain modifications of 12 the web composition to obtain the desired type and pattern of release of medica-13 ment would likewise have to be made. Tests have shown that rectal and vaginal 14 insertion of solid dosage forms according to the invention has produced sub-stantially no local irritation.

17 As mentioned above, the novel dosage units prepured in accordance with 18 the invention can be formulated or "engineered'7 to any desired release 19 pattern including sustained release. Regardless of the release pattern, the dosage units of the invention are characterized by an cxceptional uniformity 21 of release over a large number o dosuge units, e.g. ten thousand or 22 more. The variance in release rate can be o~tained in accordance with the 23 present invention by the manipulation of a number of factors such as, for example, 24 the thickness of thc web, the composition of thc web, the presence of an over-wrap or outside seal on the fabricated wcb anà its composition, how tigh~ly 26 the web is fabricated, and the like. For example, a web composition containing 27 a high contcnt of sodium carboxymcthylccllulose will normally disintegrate ' . 1, Il _g_ ..
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slowly in gastric fluids. Do~age forms fabricated from such webs by fun-fold-2 ing as will be described hereinaftcr will open or unfold upon contact with 3 gastric fluid thereby releasing the medicament loaded on the internal sur-q faces thereof very rapidly, in fact, more rapidly than conventional Sablets and S capsules presently available. However, i such a fan-folded dosage form 6 were to be sealed on the folded edges with a substance such as, for example, 7 ethylcellulose, cellulose acetate phthalate or zein which will prevent its opening 8 in gastric fluids, the medicament would become available by the gradual erosion 9 of the web thereby giving a steady, sustained release of medication. Since the dosage forms prepared in accordance with the present invention are capable 11 of releasing medication with a ~apidity superior to presently available solid 12 dosage forms, i.e. tablets and capsules, such release represents the preferred 13 ` embodiment of the present invention.

The accompanying drswings are summarized as follows:

17 Fig. 1 is block diagram of the total m~nufacturing process indicating 18 points of on-line inspection.

ao Fig. 2 is a diagrammntic representation of a system capable o effecting 21 the process depicted in Fig. 1 23 Fig. 3 is a diagrammatic representation of an arrangement for carrying 24 out the convolute winding technique of dosage form fabrication.
26 Figs. 4, 4A and Fig. 5 illustrate the rotary-forming and lamination 27 techniqucs of dos~ge form fabrication.

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Figs. 6A-GD illustratc thc finishing and sealin6 aspccts of thc f~n-2 folding technique of dosage form f~bricAtion.

4 Fi~s. 7 and 8 ure graphic illust,rations of the pattern of releasc of active ingredient from the dosage forms of the invention in comparison with a con-6 ventional solid dosage form, i.e. a capsule.

TIIE WEB

The webs capable of being utilized for deposition for medicament in 11 accordance with the present invention must meet a large, diverse number of 12 physical and chemical criteria to be acceptable in the practice of the inven-13 tion. These cri$eria can be briefly summarized as follows:

The web must be non-toxic, edible and, particularly, not have 16 an objectionable "feel" in the mounth. ln addition, the web preferably self 17 destructs or is degradable in body fluids and/or enzymes. However, the web 18 can be of non-destructible substance which is resdily eliminated by the body.
19 The web preferably is hydrophilic and readily disintegrable in water. These properties must not be adversely affected and, preferably, be enhanced at 21 the pH of gastric fluid;

23 The web must be totally inert to the medicament loaded thereto and must 24 not release any substance upon dissolution with gastric fluid which would cause an in situ incompatibility with said medicaments;

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11 1085;~5 The web must be stablc over extended periods o~ time and ut elevated .~ tcmperatures and relative humldity and gcnerally be a poor mcdium for the 3 growth or microorganisms;

The web must have acceptable resistivity properties so that powdered 6 medicament (usually possessing dielectric properties) can be loaded thereto 7 by electro6tatic deposition;
The web must po~sess acceptable workability and mechanical properties, i.e. it must possess sufficient elasticity to allow it to be drawn or cast into 11 a thin ~heet, i.e. from about 0.025mm to about 0.25mm in thickness, it must 12 possess good tensile strength and tear strength and it must have acceptable fold 13 endurance where required to withstand certain of the fabrication methods a8 14 will be discribed hereinafter;
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16 The web surface must facilitate the types of on-line analytical procedures 17 described hereinafter, be capable to being coated with and retain powdered 18 medicament electrostatically or otherwise loaded thereto and be amenable to l9 printing operations;
21 The web must be readily ~ealable by liquid and or hest sesl methods ~uch 22 as are recognized in the art. The sealing, however, must be effective at levels of 23 moisture and heat which do not adver6ely a~fect the medicament contained in 24 the dosage form. In addition, the web must possess acceptable flammability resistance so as to tolerate such sealing operations;
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27 In certain instance6 the web must possess "memory", i.e. it must have', ~
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~ ~3852~5 sufficient resiliency so that, upon contact with gastric fluids, it will very rapidly reverse the fabrication process and "open" thus releasing medication for absorption. By "opening" is meant that, for example, if the dosage form is fabricated by fall-folding it will open like a bellows, if fabrication is by convolute winding it will uncoil, and the like; and The web must possess other properties such as, for example, having acceptable taste and odor which will become apparent to those skilled in the art from the instant disclosure.
As mentioned above, the webs utilized in the present invention are 10 preferably water soluble or water dispersible. There are two basic mecha-nisms whereby the webs of the present invention are formulated to self des-truct in contact with water or gastric fluid. First, the web can contain par-ticles of substance such as, for example, casein, gelatin and the like which swell upon contact with water thereby disrupting or breaking the web. Second, the web formulation may contain both water soluble and insoluble constituents.
Upon contact with water, the soluble constituents of such a formulation will tend to go into solution and the insoluble constituents to precipitate thereby causing the web to rupture. The latter means of disrupting the web is not as `
rapid as the former. Examples of suitable water soluble constituents include methylcellulose and the like. Examples of suitable water insoluble consti-tuents include ethylcellulose, and the like.

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The web formulations utilized in prepuring the novel dosage forms 2 of the present invention are of two basic types, i.e. polymeric ~nd p~per.
3 The polymeric formulations generally co~nprise;
4 a) one or more organic film formers b) one or more plasticizers 6 c) modifiers, i.e. other ingredients optional with certain formulations 7 such as disintegrants, extenders and the like.
8 d)~ one or more fugitive solvents.
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The paper formulations generully comprise:
11 ~ a) one or more fibrous materials 12 b) one or more non-fibrous modifiers, i.e. other ingredients optional13 with certain formulations, e.g. one or more organic film formers, disintegrants, 14 extenders and the like.
c)~ a fugitive solvent 1ô
17 The film forming compound of the polymeric webs of the present 18 invention comprises one or a mixture of art-recognized, non-toxic, orgsnic 19 film formers such as, for example, natural and chemically modified starches and dextrins, proteins such as gelatin; cellulose derivatives such as sodium 21 carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose xa~hc~n ' 22 snd the like; other polysaccharides such as pectin, acacia, ~ gum, 23 guar gum, nlgin and the like; synthetics such as polyvinylpyrrolidone, polyvinyl 24 alcohol and the like. Preferred film formers are hydroxypropylcellulose and sodium carboxymethylcellulose. Although the concentration of the film forming 26 component in the polymeric web is not particulnrly critical to the practice of the invention, it has been found that between about 5% by weight and about 95%
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':`' 11~ iO85~95 by weight is prefcrred with u concentration of from about 40~6 by wei~ht to 2 about 90% by weight being mo~t prcferred.

4 The above named film forming ~ubstances are equally illustrative of the film forming component of the paper web formulations of the present invention 6 where such is present. Preferred film formers of the paper web formulations of the invention are likewise hydroxypropylcellulose and sodium carboxymethyl-8 cellulose. The concentration of the film forming ingredient in the paper web 9 formulatiolls of the invention is likewise not considered critical. However, when 6uch ingrediènt is present to act as a binder or disintegrant for the fibrous 11 ` material, it should not exceed about 40% by weight, preferably from about 296 by 12 weight to about 20% by weight and most preferably from about 4% by weight 'co about lOg6 by weight.

The fibrous ingredient of the paper web formulation6 of the invention can 16 be any of the commercially available natural or artifical fiberR which have been 17 shown by proper tests to be non-toxic. Examples of such fibers include cotton, 18 linen, cellulose, syntheticallymodifiedcellulose, rayon, texturedveget~ble 19 protein, collagen and the like.

21 To insure the required workability and mechanical properties, the polymer 22 webs utilized in the practice of the invention contain an effective amount of a - plasticizing ingredient. Such ingredient may include one or more members of 24 the group of plasticizers recognized in the art of pharmaceutical compounding such a~, for example, glycerin, the polysorbates, e.g. polysorbate 80, polysor-26 bate 60, certain mixtures of mixed mono- and di-glycerides of saturated fatty 27 acids and the like. It is preferred that such plasticizers be present in an amount;
.- ~ ~o70 " `~ 28 comprising from about 1~6by weight to about~by weight, prefcrably from about ;~J 10% by weight to about S0% by wcight of the web composition.
:', '- 1 ~35Z~5 Both polymer and paper webs m~ly cont~in one or more disintegrunts such as flre recognized as being convemtional in the art of disposnble papcr 3 such as, for example, various types of starches, casein, gel~tin and the like.
4 The webs according to the invention should contain from about 0% by weight to about 40~6 by weight preferably from about 5% by weight to about ao~ by weight 6 of disintegrant depending on the web formulation.

Further, both types of web formulations may contain one or more 9 fillers or extenders which are recognized in the art as being conventional.
Such ingredients include, for example, opacifier fillers such as titanium '!
11 dioxide, chalk, kaolin and the like, microcrystalline cellulose, calcium 12 carbonate and the like. It is to be appreciated that some of the ingredients 13 ` enumerated herein can function in more than one capacity and therefore 14 fall under more than one of the categories listed above. ~or example, calcium - 15 carbonate can function as both an opacifier and dispersant, certain starches can i6 function as binders and as disintegrants, etc.

18 In addition, both polymer and paper formulations may contain one or more 19 modifying ingredients which affect the electricfll, mechanical, optical or per-meative properties of the webs produced therefrom. Examples of such ingre-;l dients would include an electrolyte such as, for example sodium chloride, 22 potassium chloride and the like, surface active agents such as dioctyl 60dium sulfosuccinate and the like. The webs may also contain optional ingredients such 24 as pharmaceutically acceptable coloring agents, preservatives, and the like.

26 Fin~lly, both typcs of web formulations, in most instances, will contnin a fugitivc solvcnt, e.g. water, certain orgnnic solvents, for exumple, athyl alcohol 28 or combinations of such 601vents i.c. fl hydroalcoholic mixturc which is removed 29 during ~ormulntion of the web.

1~85Z95 Specific o~;amples of film compo~itions in ~ccorduncc with the present .~ invention includc the following:
3 Polymeric films th~t self-destruct in an aqucous environment due to the presence of swelling agents.
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6 IngredientPercent by Wei~ht ~drD,Y~ pr op ylmefhy/
3 7 I ~ ~5 . 69 8 cellulose 9 Acacia 19 . 44 Gelatin, extra fine, solubilized 32.08 Dioctyl Sodium Sulfosuccinate 11 , 75% aqueous solution 0.09 la litanium dioxide 1.94 13 Lecithin o . 75 14 1~0 11 Refined starch 33 . 06 16 Carboxymethylcellulose 33 . 06 17 Propylene Glycol 33.06 18 Sodium Benzoate 0 . 55 Sorbic Acid o ~q 21 111 Hydroxypropylmethylcellulose 55.19 22 Cellulose Acetate Phthalute 2.99 23 Corn Starch 28.66 24 Propylene Glycol 9 . 87 Titanium Dioxide 1.52 26 Dioctyl Sodium Sulfosuccinate 1. 52 Lecithin 0 . 25 .~
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IV Hydroxypropylmethyl- 64 . 00 3 cellulose ~ Cellulose Acetate Phthslate 3.10 S C01cium Carbon~te 21.74 B Propylene Glycol 9.06 7 Titanium Dioxide 0.91 8 Dioctyl Sodium Sulfosuccinate 0 . 91 Lecithin 0 30 . 1~ ~,', .
11 ~ All of formulstions I-IV are sealable by the application of heat and 12 pressure. Formulation IV self destructs in an aqueous environment due to the 13 presence of in~oluble polymeric agents.

Preferred paper formulations in accordance with the subject irlvention 16 comprise rom about 70%by weight to about 99%by weight, preferably from 17 about 90% by weight to about 96% by weight fiber, e.g. hardwood or softwood 18 fibers or mixtures thereof, from about 1%by weight to about 30~by weight, preferably from about 4% by weight to about 10% by weight of a di6integrsnt selected from the group consisting of sodium carboxymethylcellulose, methyl-21 cellulose, hydroxypropylcellulose, polyvinylpyrrolidone and guar gum and 22 from about 0% by weight to about 5% by weight, preferably from about 096 by 23 weight to about 2% by weight of a surfactant such as, for example, polysorbate 24 80, dioctyl sodium sulfosuccinate, sodium lauryl sulfate and thc like,.~ability of the above substances to function as disintcgrants in paper formulations i9 ..
26 considered to be unexpected in view of thc fact that~ where members of this 2~ group are utilized in paper making they are present in different quantitics and .~

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108525~5 perform a differcnt function. For example, wherein sodium carbo~;ymethyl-.~ cellulose h~ heretofore been utilized in paper making, it ha6 been utilized in 3 small quantities, i.e . O.19~ by weight or less as an aid in dispersing the fiberY
as the paper is formed. In distinct contrast, it has been found that when sodium carboxymethylcellulose or the other substances enumerated above are added in 6 large quantity, i.e. up to 30% by weight after the paper web i~ formed but while 7 it i9 still wet they will function as disintegrants the time of addition of these 8 substances is critical to the function thereof as disintegrants. The disintegrunts 9 ~re added 118 a solution preferably in the solvent utilized to prepare the paper web. lt has been found that the above named disintegrants, when added to the 11 web as herein described, coae the fibers. When the finished dosage form is 12 contacted with water, the disintegrant 6wells thus forcing the fibers to disrupt 13 the web. The surfactants, where present, acts to enhance the penetration of 14 water to the disintegrant thu~ promoting disruption.
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16 The webs utilized in accordance with the invention are formed by 17 processes conventional in the arts, e.g. the paper-making and film malcing 18 industries. For example, the polymeric webs can be cast on nn appropriate 1~ substrate, e.g. Mylar, stainless steel, release paper and the like. The webs are then dried, e.g. in a forced ~ir oven. The temperature of the drying air l I
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52~5 and length of drying time depcnd on thc nature of the ~olvent utilizcd as is ',2 recognized in the art. Most of the webs contempl~ted herein, however, are 3 dried at a temperature between about 2S and 105, preferably between about 60 and 90C.
6 A second method of forming polymeric web~ which i6 conventional in the 7 art i8 extrusion. This method i6 preferred with webs wherein the film form-8 ing ingredient is a modified food starch, hydroxypropylcellulose or other 9 extrudable polymer. The mechanical particulars of the extru~ion process, e.g.
the particular equipment utilized, the extruding force, the sh~pe and temperature 11 ~ of the orifice are considered to be within the 8kill of the art and can be 12 varied in a known manner to achieve the physical characteristics of the webs 13 to be described hereinafter .
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The paper webs of the subject invention are prepared utilizing conventional 16 paper-making machinery ~uch ~s, for example, Fourdrinier paper making machine~
17 In all cases, however, the web must be uniform in both thickness and width.
18 The webs are between about 1 and about 10 mils (about 0.003mm to about 0.03mm), lD preferably from about 1.5 to about 4.5 mils (about 0.38mm to about 0.123mm) thick. A convenient width for such webs i~ 12 inches (30cm) although the 21 width of the web is not particularly critical to the practice of the invention.
22 The web can be produced in any length. However, in view of the fact that the 2q 1~

Il 20-852~5 novel dossge forms produced in accordanc- with the invention are emminently 2 suited to high speed manufacture, the webs should be prepared in l~rgc 3 qu~ntity, e.g. 15000 feet or more which can be stored, e.g. on cores or 8pO01Ft, Reference is made to Fig. I in which is shown in block diagram form the 6 overall system process for manufacturing in large numbers the various kinds 7 of dosage forms herein described. Block 10 of Fig. 1 represents web production from formulations such as have been discussed above. As the web is produced, or shortly thereafter, it undergoes an inspection step (block 11 in Fi~. 1) where various examinations, which may be in whole or in part automated, are perîorrned11 to ensure the integrity of the web, as will be more particularly described ` 12 hereinafter. It is to be noted, however, that the inspections of the web can 13 take place as the web is formed or at Any convenient point thereafter, either by . 14 means associated with the apparatus making the web or by other apparatus, .~i 15 and may, in fact, be performed at another location.

17 The active ingredient to be deposited on the web is prepared nnd stored for 18 use in container means, as is generally illustrated at 23 in Fig. 2, which figurë"
19 illustrates, largely in schematic form, the various apparatus suitable for per-forming the steps indicated in Fig. 1. The prepared active ingredient is caused , to be forwarded to an arrangement generally indicated at 23 in Fig. 2 where the , 22 active ingredient p~rticle size reduction and control indicated at step 12 in Fig. 1 23 is performed. Although this step will be discussed in greater detail hereinafter, 24 it is intended via this step 13 and the depicted apparatus 23 to provide a uni-formity of flow in order to enable exact and uniform deposition (block 14 26 of Fig. I) of the active ingredient on the web, which is illustrated at 2427 in Fig. 2. It should be noted th~t the system cxample depictcd in Fig. 2 per-,.. .. ..

352~5 I

tnins to the deposition of dry particulate materinl onto the wcb in u dry state.It is to be clellrly understood, howcver, that the scope of this invention includes as well wet deposition of active ingredient onto the web. Fig. 2 also illustrates schematically at 21 that embodiment of the invention wherein the web is prepared and stored for later use, i.e. the web inspection step (Step 11 of Fig. 1) is performed, e.g. a8 the web is caused eO be taken 7 off of a storage roll 20. It is to be clearly understood that inspection may be made prior to the web being wound and stored as well as or in addition to being 9 perform~d where and as indicated in Fig. 2 at 21. The particulars of web inspec-tion are described in greater detail hereinafter.
11 ~ . :
12 With more particular regard to inspection means 21, inspection of the 13 uncoated web is accomplished by several methods. Holes, blemishes, and 14 physical integrity of the web may be evaluated and quantified by using a scanning laser beam and photodetector combination. The system is used in both trans-16 mission and reflection modes. The continuous helium-neon laser beam is steered 17 across the web by a mirror on a galvanometer . The mirror position i5 electroni-1~ cally controlled so that the position of any defect on the web can be located. The 19 reflected or transmitted light is detected by a linear photodiode located behind an interference filter to exclude room (stray) light. The electrical output is used 21 to count the number of defects and determine their size and distribution along the 22 length of the web. This is accomplished by analyzing the detector output signal 23 with a pulse height-width analyzer.

An alternate method capable of inspecting the web at significantly higher 26 wcb speeds is a parallel array of photodiodes positioned across the web. Ench 27 photodiode has its own threshold detector systcm and digital logic which ullows ::"' ~ ~ , ,''' ' , , ' ` 1~ 1085295 a low-resolution defect size and position locution characterization. Thc vutput .~ signal can be processed to yield approximute size distribution and the location 3 of the defects on the web.

The physical thickness of the web is measured by a parallel array of web riders mounted in precision bearings. These rollers contact the web and are 7 connected to transducers which electronically sense position to at least 1/lû,000 8 inch. A similar system of physical thickness can be made of pneumatic sensors 9 which float above the web on a fixed film of air. This system has the advantage of noncontact with the web.
''`'' 11 ., 12 Mass thickness (weight per unit area) or basis weight of the webs is 13 determined by using a noncontacting beta-ray or x-ray guage. These systems 14 measure the absorption of beta-rays or x-rays passing through the web. This absorption is related to mass thickness. In an alternate system, the electrical 16 resistance between two contacting web-riding electrodes may be used to determi 17 the basis weight of webs with known moisture content.

19 On-line analysis of moisture content can be measured by one or more of th~
following methods. First, the high dielcctric content of water allows sensitive 21 moisture determination to be made by direct microwave absorption and by radio-22 frequency dielcctric constant sensors. Low-frequency conductance measuremen~
23 can also be used to measure the amount of web moisture. Infrared spectrophoto-24 metric absorption provides a totally indepcndent moisture measuring mcthod.
Further, the optical absorption at wavclengths in the region Or 1-2 micrometers 26 will yield a specific and precise moisturc determination in a spectral region 27 ¦~ wherein t web being inspectcd is rolstively tr~nspsrent.

11 . , " , ..... . ..... . .

3S2~5 Thc web, hsving p~ssed the inspection means 21, is guided by a suitable 2 roller arrangcment shown in Fig. 2 to pa~s in close proximity to the active 3 ingrcdient deposition apparatus 24 wherein active ingredient is loaded to the we~
4 The deposition apparatus is immediately followed by means 25 schematically shown for on-line analysis/inspection, e.g. for content uniformity of active 6 ingredient, of the coated web preferably as a ~ingle sheet before the active 7 ingredient has been internalized.

A preferred method for the nondestructive on-line analysis of active ingredient deposited on webs i9 x-ray absorption. In this method, low energy 11 x-ray~ peaked to match the absorption edge of atoms deposited on the web are directed through the coated web. The absorption of the x-rays i8 related to the 13 active ingredient-plus-web absorption~ Wherein the active ingredient is 14 deposited on the web by a wet-coating process, this method of analysis tnay be utilized either before or after the drying step.

17 Since the total x-ray absorption arises from the combination of web and 18 active ingredient containing coating, it is necessary to determine the absorption 19 of the web separately. This is accomplished by means of a beta-ray gauge or an infrared spectrophotometer. Increasing sensitivity is achieved for the x-ray 21 measurement of deposited active ingredient containing atoms with increasing 22 atomic numbers. The x-rays source can be tuned by varying the accelerating 23 voltage to match the absorption edge for many atoms of interest.

Reflcctance or transmittance spectrophotomctry may also be utilized to 26 nondestructively analyze the deposited activc inE~redient on-line. Reflectlnce 77 l 1 6poctroph t mctry i~ ured in the ncur ultr; violct region to detcrmine uctive Il -a4-: . . ,, :. : .

` ~```` 1~5Z~5 ingredient loading. This technique may be used with any solid active in-gredient having an optical absorption in a suitable wavelength region.
Transmission spectrophotometry may also be used for nondestructive ' on-line analysis of active ingredient coated on webs. A suitable light source, monochromating element, and detector combination are selected for wave~ength regions where the active ingredient selectively absorbs. This must be in a spectral region where the web itself does not strongly absorb.
Such regions for webs of the present invention occur in the near-infrared and ;
functional group infrared regions of the spectrum. A rapid wavelength scan-ning system is used to sweep over a small wavelength region of interest. The ~i signal from the detector is time-averaged over several scans to reduce the ' effects of noise. The signal data are then processed to give a first deri-, ~ . .
vative of transmission with respect to wavelength for increased sensitivity.
This is done in a similar fashion for other wavelength regions which are sensitive to other components in the system. Thus water content, basic weight ;
of the web as well as active ingredient content can be determined simultane- -~
ously.
Another method for analysis of active ingredient loading is molecular fluorescence. Excitation radiation in the ultraviolet or visible region of the spectrum is provided by a suitable filter combination. The fluorescence from :' .
:

:- `

thc active ingrcdient is detccted by a wide-band filter-detector combination .~ matching the fluorscence peak; a blocking filtcr 18 used to remove the excitstion encrgy. The detector for this method is preferably a photon counter, which 4 counts individual photo events, providing high sensitivity and linearity at low levels of illumination. In this method of ~Inalysis, precautions must be taken 6 to limit the photodegradation of the active ingredient by the excitation radiation.

8 The coated web may be stored for a time or, preferably, directly forwarded 9 to means or fabrication (step 16 of Fig. 1) and unitizing (step 17 of Fig. 1) to 10 form dosage forms which means are illustrated in Fig. a ~s a series of knives 11 26 for slicing the coated web into a multiplicity of endless strips, followed by 12 fabricating and unitizing means 27 of the lamination type, i.e. the endless strips 13 are stacked one on another to form an endles~ stack which is pressed and 14 ultimately unitized in accordance with the invention as hereinafter described.

16 The unitized dosage forms are then finished and packed by appropriate 17 apparatus (step 18 of Fig. 1) schematically illustrated at 28 and 29 in Fig. a, for 18 subsequent distribution. Appropriate inspection (at e.g. 30 in Fig. 2) is 1~ performed in connection with this step. The purpose of the final inspection of individual dosage units is to verify size, shape, integrity, identity, presence snd 21 accuracy of printing, and active ingredient content. All of this inspection is 22 done non-destructively except for active ingredient content. In order to analyze 23 for active ingredient content and performance characteristics, a statistically `~ 5Z~5 :

appropriate s~mple of dosage units is removed from the production line and destructively analyzed both for potency snd performance, e.g. dissolution 3 chsracteristics, by solution spectrophotometry a~ will be discussed hereinsfter.

An optical scanning system may be used to inspect all the production units 6 for size, shape, integrity, identity, and the presence and accuracy of printing.
The system comprise6 a ~uitable light source and a matrix of photodetectors 8 or a T.V. camera. A computer is used to process the signals from the optical system. Suitable algorithms are used to determine the acceptability of the dosage units. Another method employs a comparison of the sample im~ge with a standa~d 12 ~ image b~r means of an image-masking technique.
13 In another method for lOOg~ inspection, an optical transform of the image of 14 the dosage unit is made. The Fourier trans~orm spectrum, the po~ver spectrum.
or other suitable tran~form i8 compared with a similar transform of a standard by 16 means of a computer.

18 Prior to the finishing step, stcp 19 (Fig. 1) of on-line analysis for dis-19 solution arld content uniformity if~ performed by suit~bly arranged apparatus ao not particularly illustrated, which apparatus may include and/or by controlled 21 by computer or similar central processing or logic means . A ~sampling 22 mechanism removes one dosage unit at a time from the end of the production 23 line at a rate of 25 to 120 units/min., preferably at a rate of 40-60 units/min.
24 Each unit is sequentially transferred to a conYentional automatic weighing device ` ' ~7 11 )85Z95 whcrein it is weighed by nondestructive mcans and the inform~tion storcd.
Randomly-selectcd units are then scquentiully placcd in a convcntional automatic3 analyzing system. The dosage unit is ~;tirred in a suitable ~olvent for the active 4 ingredient at an appropriate rate. The amount of active ingredient dissolved at tj minus the amount dissolved at ti divided by tj-ti is taken us the rate of 6 dissolution. The appropriate time intervul (tj-ti) has been previously chosen and will vary with individual medicaments. A suitable time interval might range 8 from 5 seconds to 2 minutes or more. The sample is then continuously stirred g for a sufficient time to allow for all of the active ingredient to be dissolved after which the solvent is analyzed for content of active ingredient. The amount 11 of ac$i~re ingredient in this analysis plu6 the amo~lnts from samples ti and tj is 12 the total present in the dosage form. This information is also recorded and stored.
13 If the weight, thickness, dis601ution rate, and analysi6 of the medicament 14 content fall within previously defined limits, the units are deemed acceptable.
If the readings do not fall within these limits, the units produced beginnin~
16 with the negative analy6is and ending with the next positive analysis are quaran-i7 tined for further evaluation.

19 It is to be noted in Fig. 1 that further provision is made for monitoring functions to be performed in accordance with this invention as are described 21 hereinafter. Regarding the web inspection step, it is intended, for example, 22 that continuous monitoring inspection of the web be made from the standpoint 23 of the web color, thickness, continuity, soil spots and defects of virtually any 24 kind. These functions may be performed by electronic and/or optical instruments 1~

11 11~5Z~5 ¦~ as well as ~ u.l ob~erv~tion.

3 Inspection of the web includes the actual placing of a "il8g" on the web 4 wherever a fault or defect is detected. Addltionally, apparutus may be provided such that, whenever a defect is detected in the web a printout is genera~ed, either 6 automatically or under operation control, indicating that on the web at certain 7 distance downstream a defect of some sort exists, which printout would include 8 an identification of the type of defect, such as a hole, blackspot, blemish etc. .
g The means for generating the printout can be the same apparatus actually, 11 nagging the web per se. Such apparatus is considered conventional in fabric 12 manufacturing and fabric inspection, for example, with the exception that the 13 handling snd inspection of the web would, in the instant case, be performed in 14 accordance with good manufacturing practices.
16 In addition, by the same or additional conventional inspection apparatu~
17 the web thickness would be measured. This could take the form of a visual18 display involving an operator or could be a detecting device coupled to a logic 19 arrangement having upper and lower limits for web thickness, wherein if the thickness of the web violates one of the limits, there will also be effected a 21 printout and a nag placed on the web as described above. One form of apparatus 22 for providing thickness measuring of the web could take the form of an x-ray 23 or a beta ray gauge or some 6imilar device for measuring the mass thickness 24 of the web.
2~ ln the case of step 13 of Fig. 1 regarding particle si~.e reduction and flow 27 control, it is intended that monitoring functions be performed as described -2~-

5;~5 in the following. In accordnnce with the invention, notwithstancling thut the 2 unloaded web itself has been monitorcd for dcfects nnd thiclcness, similar . monitorin6 is contemplated following losding of the web with active ingredient(s) .
4 For example, x-ray gauge apparatus would, again, be applicable to determine S the loaded web thickness, which thickness, in comparison to the earlier

6 determined unloaded web thickness, would enable conclusions to be derived .

7 regarding the amount of active ingredient loaded to the web . Additionally,8 it is within the scope of this invention to provide actual mass monitoring means g in order to determine the arnount of sctive ingredient loaded to the web.
It should be understood that performance of coated-web inspection could be 11 effected by routing the coated web back through the same apparatus performing ~-12 the web inspection in connection with step 11 in Fig. 1.

14 The active ingredient deposition system ~reference 14 in Fig. 1) is con-trolled by feedback from the on line analysis of active ingredient content on the 16 web. For example, electricsl signals from the on-line analyzer (digital) or 17 analog) analyzing acSive ingredient loading (weight of active ingredient area 18 of coated web) are used in a feedback mode (reference designator 15 Fig. 1) 19 to control the amount of active ingredient applied to the web irl the deposition process; These feedback signals are fed, for example, to a minicomputer 21 which produces a suitable correction signal to the cleposition process.
22 The correction signal causes either an increase or a decrease in the active 23 ingredient loacling so as to maintain the loading within a narrow range around 24 the target value. For example, in the dry deposition process, the activc ingredient powder s introduced into the deposition apparatus. Thus, the 26 correction signal is used to control the feed rate and, conse~luently, the active 27 ingredicnt loading.
. . I

In thc wet (leposition proces~, the correction si~nal mny be utilizcd, .~ for example, to v~ry the ~mount of thc coating formulation wllich is applicd 3 to the web. For exs~nple, the gap between metering roller~ or between a 4 meterin~ knife and application roller i~I varied to change the active ingredient S loading. In reverse roll coating, the rotational speed of the ~pplication roller 6 is varied to change the active ingredient loading. Another means of control in wet deposition is by variation of the concentration of active ingredient in

8 the coating liquid. Two liquid formulations containing different concentrations

9 of active ingredient are mixed in the required proportions to supply the correct concentration; the ratio of the two formulations may then be varied to accuratel~r 11 . control active ingredient loading.
la 13 Deposition of Medicament on the Web 14 .
The methods of "incorporating" active ingredient into the novel dosage 16 forms of the present invention constitute a radical departure from methods of 17 incorporat;on active ingredients into conventional solid dosage forms, e.g.
18 tablets, capsules, dragees, suppositories, etc. While the methods and equip-19 ment utilized in the methods of the invention may vary somewhat, the overall prime object is uniformity of deposition, i.e. to deposit active ingredient on the 21 moving web surfaces in an exceptionally uniform manner. The manner of active 22 ingredient deposition utilized in accordance with the present invention is uni~ue 23 and possesses a number of advantages over manufacturing procedures commonly 24 utilized in the pharmaceutical industry.

. .. .... . I' 35Z~5 In view of the fact that the active ingredient is deposited on or substantially on the surface of an edible web which is then fabricated to com-pletely internalize it, there is no need for common pharmaceutical excipients, fillers, preservatives and the like to be admixed with the active ingredient thus eliminating a cost and "nore importantly, a source o~ potential incom-patibilities and quality control problems. The web3 in accordance with the present invention, is loaded with a uniform coating of active ingredient and is then divided into individual dosage forms by linear or geometric subdivision thereby effecting a level of uniformity of strength of active ingredient over a large number of dosage units which is substantially superior to the batch -~
requirements now accepted in the pharmaceutical industry. In distinct con-trast, conventional pharmaceutical manufacturing oprations require that the active ingredients and suitable therapeutically inert pharmaceutical adjunct ~-materials are prepared in a large quantity and subdivided volumetrically for filling into capsules or compression into tablets. Utilizing the manufactur- -~
ing methods of the present invention, it is therefore possible to reduce the amount of excess active ingredient present to assure label dosage from the presently accepted level of from 5% to 10% by weight to approximately 1% to 5% by weight thereby realizing a substantial saving particularly when compound-ing very expensive active substances, e.g. certain hormones and antibiotics.
Finally, the method of depositing or loading the active ingredient to the web in accordance with the present invention allows for continuous, on-line, non-destructive testing of the dosage by physical parameters thereby facilitating superior uniformity of amount of active ingredient over a large number of dosage forms.
The active ingredient may be loaded to the web in either wet or dry form, with dry form being preferred. In either instance, the active ingredi-ent is deposited in a form susceptible to analysis as Nlll be described herein-after, i.e. a finely particulate form. The particle size is in the submicron range .,. ~

,: ~

10 8 52~ 5 and can also bc within a narrow aize ran~e from I up to 100 microns. Particlcs 2 in the submicron range have hcretofore bcen considered as being too fine for 3 the production of pharmaceutical tablets without first being subjected to 4 techniques such as granulation which substantially incrcases psrticle size and S which also adds excipient matter to the active ingredient. The technology of the invention facilitates the use of such ultrafine particles without the need to 7 resort to such techniques and/or the addition of excipient matter. The active 8 ingredient is deposited as a very uniform coating on the web 8S it is being 9 moved in an automated manufacturing system.
:,10 . ,

11 The preferred method of deposition of active ingredient on the web wherein

12 the active ingredient is a dry form is powder cloud electrostatic deposition

13 utilizing techniques generally recognized in certain non-pharmaceutical arts.

14 Generally, this method requires passage of the web through an electro-~3 15 static field in a suitable chamber. Finely particulate active ingredient iS~q 16 introduced into the chamber via, for example, a forced air stream and is 17 deposited on the web as it passes over an oppositely charged roller. It is 18 readily apparent that this is an oversimplification. However, apparatus 19 required to accomplish this result is known in certain non-pharmaceutical fields such as the production of adhesives and adhcsive papers. For a success-21 ful deposition to take place, it will be apparent that the web must have a resis-22 tivity capable of enabling tlle deposition thercon of dielectric particlcs. Addi-23 tives which can be prescnt in the web formulation to enhance the proper electri-24 cal properties thereof have been discussed above. In a number of instances, ;~
it has been found that. prior to clcctrostatic deposition of active ingredient 26 powder, it is necessary to coat the web with a substancc which will enhance 27 the adherence of the powder thereto. Examples of such subs~ances include '~'.
': ' . . .

.. , ,.~, , ,. ~ : : ..

~85Z~5 curboxymethylccllulosc, mcthylccllulose ~nd thc like. These adhcrence 2 enharlcing substances may be upplicd to the webs in a conventional manncr, 3 e.g. by applying n solution in a fugitive solvent ~uch a~ wutcr and drying with, 4 e.g. he~ted ~ir. The application of a costing to the web to insure adherence of the active substance is then immediately foliowed on-line by the coating or 6 "loading" of the web with active substunce. The adhesive is then activated~
7 bind the particles of active substance to the web. This i~ accompli6hed by 8 applying heat, pressure, moisture or a suitable combination thereof to the 9 loaded web. In addition to the electrostatic powder cloud deposition method, fine particulate active ingredient may be coated onto the web in a dry state by F/ec~rog 0~5cl~c~1n 11 ~ _~powder coating. In this method, the particles of active 12 ingredient are electrically charged by exposure to corona discharge and pro-13 pelled by a gas stream into an electrically insulated chamber. The web is 14 passed through this chamber on a metallic surface which is either grounded lS or charged with opposite polarity to that of the charged cloud of particles 16 of active substances. The electric field between these particles and the meta-17 llic surface attracts them to the web and deposits them thereon.

l9 Further in accordance with the present invention, active ingredient may be coated onto the web in the form of a solution on a suspension of finely 21 divided medicament, i.e. a collodial suspension. The liquid utilized for 22 these operation~ can be water, an organic solvcnt, e.g. ethanol or a 23 hydroalcoholic solvent. A preferred method of loading active ingredient in 24 a liquid form onto a moving web is electrostatic jet spray deposition. In this method, the active ingredient containing solution or suspension is metcred into 26 an appuratus which projects a spray of microdroplets which are concentrated 27 on a particular urea of the web through the use of a defincd area electrostatic , .. . :: .. .
. . ,:, ::

~(3 85Z~5 field. This method has given very good results where small quantities of active ingredients such as, for example, hormones or enzymes are to be loaded on the web. By small quantities is meant active substances having a usual dosage of less than one milligram.
In addition to electrostatic jet spray deposition, certain other coating techniques recognized in other arts as being amenable to the coating - of a substrate with a liquid may be utilized in loading the web with active ingredient. For example, the paper web may be passed under a roll which is immersed in a bath of saturating fluid. As the web passes the roller, the excess fluid is "wiped" from the web by another roller, a jet of air, a rubber wiping bar, a wire-wound rod, i.e. a Meier rod, or the like. In this instance there is some penetration of the web by the solution, particularly if the solvent utilized to solubilize or suspend the active ingredient is the same or similar to that utilized to form the paper web.
It will be appreciated that, while it is the object of the present invention to load the active ingredient to the surface of the web, some pene- -tration of the web may result either from the use of a fugitive liquid carrier for the active ingredient or by the application of heat and/or pressure to ` the web to seal it. Simple experimentation with these factors, e.g. fugitive liquids, will determine the percentage of active substance loaded to the web which may be absorbed therein. Once this parameter is established, the on-line testing apparatus as described herein can be adjusted accordingly. Where any appreciable amount of active substance is absorbed into the web it it neces- ;
sary to have unloaded web, i.e. web without active ingredient for the outer surface of the dosage unit thus preventing loss of active ingredient through exposure to deteriorating forces such as air and moisture. Obvious modifica-tion of the fabricating processes to be described hereinafter will acccom-plish this result.
, - :.

, '' .
:
.~

; " 1~8SZ~5 , As stated above, one of the obvious advantages of the dosage forms of the present invention is that pharmaceutically active substance can be for-mulated into a stable dosage form without being admixed with conventional pharmaceutical excipients which are usually present in conventional solid dosage forms in quantities far exceeding the amount of active substance. It will be appreciated, however, that small amounts of inert substances may of necessity be loaded on to the webs with the active substance in accordance with the invention as described above. For example, wherein the active sub-stance is loaded to the web in dry form, a small quantity, i.e. from about 0%
by weight to about 10% by weight, preferably from about 1/~% by weight to about 2% by weight of the active substance, of a glidant may be homogeneously admixed therewith. The purpose of the glidant is to facilitate the flow of the powdered active substance through the deposition apparatus. Suitable glidants include, for example, finely particulate siliceous preparations such : .. :
as the colloidal silica marketed under the trademark Cab-0-Sil by the Cabot ~` Corp., Boston, Mass., talc, finely particulate starch preparations, e.g.
DriFlo* by National Starch, Inc. and the like. It can be appreciated that the inclusion of a glidant and the quantity thereof will depend on the crystal-line structure and flow properties of the active substance. In certain in-stances, a preservative may be admixed with the active substance. However, ' wherein the active substance is loaded to the web in dry form, this is usually not required. Further, it is within the scope of the present invention to admix the adhesive substances referred to above with the active substance when applying in wet form and wherein both adhesive and active substance are com-patible with the same liquid carrier. In most instances, however, the adhesive substances are utilized as described above wherein the active sub-stance is loaded to the web in dry form to enhance adherence thereto. In either instance, said adhesive substance may be present in from 0% by weight to about 100% by weight, preferably from 0% by weight to about 30% weight based on the weight of said medicaments.
* Trademark ~ - 36 -:,:
. ~ . , .. , , : , ,,, . ;, , " . ;, , ~ :.

852~5 . ~

The amount of active substance loaded to the web in accordance with the present invention will vary according to the dosage of sa~d substance, the area of the web to be coated, the thickness of the coating and the like.
Additional factors affecting the amount of drug loaded to the web are the method of loading utilized, the parameters dictated by the fabrication process to be described herein after and the type and sensitivity of the on-line test-ing equipment utilized. In all instances, however, the amount of active substance loaded to the web is such that when the loaded web has been fabri-cated and unitized, each resultant unit will contain a therapeutically efficacious dosage thereof. As an example of the latter criteria, wherein the analysis of drug loading uniformity is carried out utilizing spectrophoto-metry employing photoncounting techniques to measure the ultraviolet absorption ~s of the active substance of the web, the thickness of the active substance ;
coating cannot exceed 0.005 centimeter. In any event, the amount of active ~
substance loaded to the web is always expressed in milligrams or micrograms -:
; per square centimeter of web. This is determined or the total web surface even though in some instances it is necessary to leave a margin of uncoated web to be utilized for sealing the dosage form. The capability of the webs to `~ receive and internalize active substance in accordance with the subject invention is expressed as the web conversion factor (WCF) and is calculated by the following formula.
Surface area of web exposed to drug . ~ .
~ = Neb conversion factor.
.:, -~ Maximum area of final dosage form .~, .
For example, if web measuring 15.25 cm x l.0 cm is exposed to drug -l and is fabricated to a dosage form measuring 0.5 cm by 1.0 cm then;
.:
` 15 25 x 1.0 , -- 30 = 30.5 Web conversion factor.
0.5 x 1.0 ~ - 37 -:..

8SZ~S

Fabrication The next step in the preparation of the novel dosage forms according to the invention is the forming or fabrication step. As utilized herein, the term "fabrication" indicates transposing the web as initially formed into a solid geometric form of predetermined shape divisible into a plurality of unit dosage forms. This step may take place, as is the case with regard to the steps above-described in a continuous manufacturing procedure at high speed. This step transforms the loaded flat web into a shaped geometric form and, generally, substantially internalizes the active ingredicnt within a protective coating of web. The formed web is then unitized and finished to produce pharmaceuticaIly pleasing unit dosage forms suitable for oral ingestion.It should be noted that, in a preferred operation unitizing would occur along with or immediately following fabrication.
In accordance with the presentinvention, there are several different methods of fabrication, among which can be named extrusion tubing, multiple ` ;~
- ribbon forming, over wrapped rope forming9 die forming and the like. The four principal techniques of forming or fabricating the web coated with active sub-~`~ -` stance are: convolute winding, rotary forming, fan--Folding and lamination.
,1, These four principal techniques are discussed in detail below.
:., ~, 20 Before discussing the individual fabrication techniques for the . ~, .
-~ invention in detail, the various criteria for an acceptable technique should r ~ be reviewed. The fabrication or forming technique should be amenable to ''rj:
high speed manufacturing operations and produce a geometric form to exacting ` specifications of uniformity. The process must be capable of substantially ; internalizing the active substance. Finally, the fabrication or forming ;i process must not put excessive stress on the webs so as to deform or tear ~, 1 them and must not dislodge a substantial quantity of "~`
~i~ - 38 -.;,',, :
' :, - :
~' ` ~985Z~5 activc substance from the web. E~ch of the forming processe6 discussell 2 hereinartcr meet these critcria.

The first principal technique to be discus6ed concerns convolute winding of a moving web. It is perhaps appropriate to distinguish between convolute 6 winding and 6piral winding as recognized, for example, in the p~per-converting 7 industry. In spiral winding, the paper is fed to the spiral windin~ machine 8 from several rolls where it i6 usually in coils that are 1/2 cm to 2 cm wide.
9 The continuous strips of paper from each roll are coiled around a cyli~ldrical mandrel which is supported at one end. The strips are coiled in such a way 11 that they overlap. An adhesive is applied to each strip of paper and the over-12 lapping strips from 8 continuous spiral as they are wound around the mandrel.
13 - The roll thus-formed i8 caused eO rotate about the mandrel by the action of a 14 continuous belt which also forces the paper roll forward toward the unsupported end of the mandrel. At the end of the mandrel, the tube thus-formed is cut into 16 desired lengths by the intermittent action of a high-speed knife. Paper which Iq 17 converted in this w~y would always have a hole in the middle by virtue of the 18 mandrel upon which it is formed. In the convolute-winding proccss, there is no - 1~ mandrel, and, therefore, it is not necessary nor desirable to have a hole in the center of the formed rod. In fact, it i6 expressly intended by this invention 21 to e~limit4~eliminate altogether this central hollow ~rea.

23 Reference is made to Fig. 3 which diagrammatically illustrates one example 24 of convolute winding. In the convolute winding process of Fig 3, the coutod or loaded web 61 is fed from a single roll through A system comprising, for 26 examplc, gllide wires S2 and roller 63 to a cutter ar rangement 64 which cuts the 27 web transvcrsely into dèsired len6ths, usually from about 12 cm to 25 cm in ; Il 3~ `

5;~5 .. :

length. The sections of web are then guided into a corrugating roller arrange-ment 65 wherein a corrugating roller forms a series of creases by pushing the web against a soft rubber roller. As a result of the corrugating action, the individual sections of web are formed or curled into loosely wound coils. The loosely curled webs emerging from the corrugating roller arrangement are then passed between a stationary surface cmd a moving surface, wherein the space between the two surfaces is gradually decreased along the course of travel of the curled webs. The stationary and moving surfaces may be in the form of two concentric cylinders, wherein one is stationary and the other rotates relative to the stationary cylinder, or, as shown in Figure 2 they may be in the form of a flat fixed plate 67 as the stationary surface and a moving belt 66 as the non-stationary surface. As the sections of web as loosely wound rods pass between the moving and stationary surfaces, they are wound tightly until a firm rod is formed. By appropriate adjustment of the spacing between the two surfaces, the rod can be wound tightly enough to eliminate any hole in the middle. It will, of course, be appreciated that, if desired, the spacing can be made so that a hole of desired size is left in the middle of the formed rod. -~
The rod can be sealed by several methods. First, it has been found that the conventional process of making, e.g. confectionary sticks is unaccept- `--- able in the practice of the present invention. In the conventional method ~ , .
the moving surfacesthat come in contact with the web during rod formation , . ! ~
are sprayed or coated with water to contact a large portion of the web. The amount of water absorbed by the web, about 18% by weight, is unacceptable for the preparation of the unit dosage forms of the invention due to pos- ;
sible deleterious effect on the adhesion of the medicament to the web as well as on the medicament itself. Further, the rods formed by this conven-tional process have been found for the most part to be too ` " .;' ' ' 1(1185Z95 tightly sealcd to givc n ~ood rclcllse of mcdicament in the body. It has bccn 2 discovercd in nccordance with thc prcsent invcntion that spruying apploximately 3 the sume portions of the web ~s in the conventional process with a suSficient 4 umount of a fine spray of water to merely d~mpell it snd rapidly drying the rods after formation yields final dosage forms possessing acceptable uniformity and 6 rate of release of medicament as well as stability in terms of the active ingrcdient;
7 with the obvious exception of those medicaments which are recognized in the art 8 of pharmaceutical compounding as being highly sensitive to the presence of 9 moisture .
`, '10 ,~
11 Second, the rods may be sealed by the application of a piece of heat- ;
12 sealable edible polymer to the trailing edge of each sheet of web or the trailing 13 edge of each sheet is coated with a heat-seslable, edible polymer directly nfter ~4 the cut is made from the endless web. Alternately, a heat-sealable polymer may b applied over the entire section of web either as a separate sheet or as a uniform 16 coating. Suitable polymeric material would include, ~or example, a water-soluble 17 polyoxyethylcne or cellulose ether derivative containing a plasticizer such as is 18 described above. After the rods are tightly wound, they are in such an instancq~
1~ made to pass under a heated plate where both heat and pressure are applied to cffect a seal. Yor example, a portion of fixed plate 67 could contain a heated 21 section .

~4 ,: ..

~ 1~8~ 5 Altern~tcly, thc rods, aftcr formation, may be sealed by the application of watcr or an ~dhefiive to the outer layer(s) or web. Preferably~ wuter is uscd3 as the scaling ngcnt. This method would likcly requirc thc presence of sub-~11 stances in or on the wcb composition, for example, starches or starch deriva-S tives, which would form a seal through subsequent drying or with the ~pplication p,~ess~re 6 of heat and~w.

The method illustrated in Fig. 3, for purposes of example, provides 9 for a water spray 68 to contact the outer surface of the endless belt 66 along to lower, return portion therof, 6uch that the belt surface contacted by 11 the rolled web sections retains only enough water, droplets to effect a proper 12 seal of the rods. The water could also be applied to the tightly wound rods, 13 ` for example by passing them under a water transfer roller, a porous plate through 14 which a metered quantity of water is uniformly applied to the total length of the rodq, or a sponge arranged to apply water to the outer surfuces of the rods. The 16 rods could then be caused to pass between a further section of the moving and stationary surfaces where pressure or pressure and heat may be applied to 18 effect the completed seul.
'` 1~ . ':

This general method of effecting a water seal is deemed clearly superior 21 to known methods of forming, for exumple, confectionery sticks as described 22 above. With the water application methods as above-described the total 23 ;

27 .

..

,, ,, . ~ . . . . .

`1 ~ 5 umount of wutcr applicd to cuch rod is lcss thun thnt upplicd by known mcthod~.
As a r~sult, the amount of watcr to bc removed during sul)scqucnt drying uf the 3 rods ifi subst~ntially les~ than thut gener~lly rcc~uired with known methods.
The rods thus-formed ure each as long us the width of the web of the 6 supply roll. This width is typically 20 to 40 cm . After each rod ;s sealcd, it is cnused to move into contact with, for example, ultrasharp knives 69 (Fig. 3) via the belt 66 where it is unitized, i.e. the rod is cut to desired 9 lengths. Methods for unitizing and finishing these rods to final dosage forms ~re discussed below in further detail.
` 11 12 A second forming or fabrication method to be considcred is generally 13 identified as rotary forming. This method can take several specific forms.
14 This method may be considered as being related to the more generic lamination method in that, in this method, stacks of web loaded with active substance in 16 endles~ strip or rod arrangements are initially prepared either by fan-folding of 17 lamination, both of which are discussed hereinafter. In one specific rotary form-S-fr~p ~ ~?
18 ing method, as illustrated in Fig. 4, a continuous, relatively thick ~ ~f ac/~el w e b 19 ~of web 70 loaded with active substance is passed between a pair of press rollers 71. The continuous thusly formed or pressed laminated stack 72 is fed 21 to R second station, i.e. a rod shaping and densifying station, comprising, 22 for example, one or morc spring loaded stainless steel rollers 73 having a 23 circumferential edge shuped to transform the strap into a plurality of contin-24 uous rods 74, or largely circular or other desired cross-section. The rods 74 shaped thereby into desired geometric form are then passed through a 27 ~

' ';' . , . . ~ .,, ' ': ' '' ~ 5152~S

third rotary station where, for example, one or more pairs of suitably arranged rollers unitizes the rods into individual doses. This may be follow- ;
ed by other suitable printing and finishing operations as are more particularly described hereinafter. It should be noted that the printing operation could be carried out in the unitizing step involving the third set of rollers 75.
, Another example of rotary forming is shown in Figure 5 wherein the formed endless stack (strip or rod) 81 is continuously indented at regular ' intervals by reciprocating die blocks 82 and/or a pair of suitable heated rollers 83 to provide ultimately rounded corners in the final dosage units, such that the output of the rotary dosage forming station is a continuous chain of end-connected dosage units 85. As with all or the various methods of rotary forming according to the invention, the thusly altered rods are passed ~;~
`i through printing and unitizing stations or subassemblies, all at high-speed.
In another closely related rotary forming technique, the continuous -~ stack is fed into a rotary shaping and densifying assembly comprised as before ", of, for example, one or more pairs of stainless steel rollers. The layers of web, which may be made from layers of paper and polymer film, are heated and compressed into a continuous stack. It is preferable that the outer layers of the stack be paper, for example, to prevent sticking of the stack assembly to the heated rolls. During this densifying operation, the layers of web are bounded together as a unit which reduces shifting of the layers and splitting of the edges during subsequent side-and end-forming operations. Next, the ends of the dosage unit are formed by feeding the continuous rectangular stack produced at the densifying station into a second station where the ends of the dosage units are formed by a pair of heated rollers which may have shaped, transversely-oriented cutters located on the rollers faces. The cut ends of -~
the dos-~ - 44 -)~ , .~ -,, ~ I .

,. .. . . . .. . . .

11 1085Z~35 agc units are shupcd and sealcd by the hcat from the rolls. Thc configuru-2 tion of the end cuttcr detcrmincs thc shapc of the cnds of the dosa~e units.
3 The shape of the end cuts is dcsigned to providc a smooth trunsition with the side cuts of the dosage units which are performed in the next station.
S
S The sides of the dosage units are formed in the laminated end-formed,7 cut material stack with a third pair of heated rolls. These rolls may have angular 8 grooves with raised cutting edges. The configuration of the groovcs in the 9 roll faces forms a desired dosage unit cross-section. Heat and pressure applied from the ridge-lilce cutting elements on the rolls seals the sides of the dosage11 units into a smooth surface.

13 The rotary-forming method of dosage unit fabrication illustrated in ~4 Fig. 5 consists, therefore, of three primary stations, viz. B pre-densifica-tion station, an end-forming station, and a side-forming st~tion. Fach of 16 these stations consists of a set of rollers, preferably heated, through which i7 the continuous web stack i6 passed. The configuration of the outside surface, lB i.e. the face of the rollers at each of the stations is different, depending on 1~ the particular station and the result to be accomplished. V~rious additional operations, such as additional cutting, printing, or finishing fiteps can be 21 performed between or at the three stations described. These operations are 22 described further below.

24 It is to b2 noted that it is within the scope of this invention to provide one or more o~ the various steps in the rotary formin~ method simultaneously, 26 and, in fact, perform on the cndless laminate input strap, via a singlc pair 27 ~ of, lor exsm e, bprine-looded, hested cooper=ting rollers, all Or the vsrious ll - 44R

sz~

nbovc-discusscd steps, i.e. rod-rormin~, dosnge-forming, uniti~ing and 2 even printin~.

The ~bove-described third example of rotary forming readily lcnds itselr to nn example of combining two or more of the outlincd steps into one.
6 Such is illustrQted in Fig. 4A wherein essentially the laminating press and 7 rod-forming steps of the ebove-discussed ~hird rotary forming method and 8 slso the method as illustrated in Fig. 4 are combined, for example, through the 9 use of a single pair of heated, pressing and cutting rollers (not particularly shown) which simultaneously press the laminate feed and end cut it into a 11 ~ shape resemblin~ a side view of a plurality of stacked doughnuts. These 12 end cut section6 are then immediately fed to a unitizer which provides the longi-13 tudinal cuts enabling the individual dosages to be realized. The printing step, 14 for example, eould also be performed at this latter station. It is also within j the concept of the present invention to p~ck~ge the unitized dosage forms 16 directly as they come from the unitizing operntion, for example, by inserting i~
17 them into blister strips by apparatus considered conventional in the art~

1~ A third method of forming dosnge forms in accordance with the present invention is the fan-folding technique. One could also classify the fan-folding 21 technique as being a form of lamination in a general sense. In this method, ¦
22 a web up to, for example, 30 cm wide is first abricated to internalize the 23 uctive ingredient loaded thereon. This may be nccomplished either by initially ~4 folding thc web in half or by lnminating two coated webs with the coated sur- ~ I
fuccs fncing. ~ stack of more thnn onc pnir of webs laminnted in this manner mny !
26 be utillzcd, the webs mny initinlly bc formcd, for example, to a grenter width, ~7 i.e. up to 60 cm and, following lamination, divided to form two or more widths of -q5-52~

a size described for the fan-folding operation, i.e. from about 1 cm to about

15 cm.
After the coated web has been initially folded or laminated as des-cribed above, it is then passed through scoring rolls where it is scored in preparation for the fan-folding operation. The scoring rolls may or may not be powered. The web is basically moved by pulling rolls. Scoring can be accomplished, for example, by spring-loading one of the pair of scoring rolls.
Since the web folds preferentially in the direction of the score rings which impressinto the web material, the score rings may be positioned alternately in the upper and lower rolls in accordance with the desired fan-fold pattern.
The scored web then passes into a fan-folding chute having folding blades which begin to gently bend the web at point of contact and constrict both in width and overlap so that the web is reasonably tightly folded at the dis-charge end. At the end of the fold chute is a means for pulling the web through the scoring and folding apparatus such as, for example, a pair of stainless steel, spring-loaded driven rollers. This serves a dual function, i.e. the ~eb is moved through the folding apparatus and the folded web is compacted into a continuous, solid geometric form. It is, of course, within the scope of this invention to combine the pulling means with means for seal-ing the web. However, the fan-folded web may be sealed by other methods as will be described hereinafter. The sealed webs may be unitized in a number of ways such as the rotary forming method described above.
rn Figures 6A-6D one fan-folded dosage form technique is illustrated ~herein the initial fan-folded webs 91 are assembled in perforations 92A of cooperating shape in a therapeutically inert web structure, preferably compris-ed of paper, identified as center strap 92. This "loaded" center strap bearing ; .

, :

3S2~ ~
;
.
` the fan-folded webs is then sandwiched between outer straps of web 93 to form - a composite laminated structure. This composite endless laminated strap is then fed to, for example a rotary dosage forming unit or sta*ion not unlike ; that of unit 83 of Figure 5, wherein the strap is caused to take on the appearance of that shown in Figure 6B. Finally, or simultaneously with the step performed in relation to Figure 6B, the unitizing step is performed, rendering individual dosages such as illustrated in Figure 6C. Figure 6D ~;
illustrates in cross section the dosage form illustrated in Figure 6C. Figure ;~ -6D shows how the fan-folded webs 91 are completely internalized and that, e.g.
the center strap 92 is forced by the molding process outwardly somewhat so that some of it is exposed between the edges of outer straps 93 which are ~ -sealed thereto. It should be noted that, preferably, outer straps 93 and ~-~
center strap 92 are free of any active ingredient thereby ensuring that none of the active ingredient will be present on any exterior surface of the in-dividual dosage forms.
The fourth principal forming method contemplated by this invention : .
is the lamination method generally alluded to hereinbefore. In this method, between about 20 and 60 rolls of web are first simultaneously unwound from a -multiple-reel unwind stand and then guided together to form a continuous rod.
The 20 to 60 layers of web may all be paper-like material with an appropriate coating to facilitate sealing in a subsequent step, or they may be a laminate ~; of a paper-like web and a heat-sealable, edible polymer web, or they may con-sist of one or more paper-like webs alternately interspersed with heat-sealable, edible polymer webs. Suitable polymeric materials include, for ~: example, a ~ater-soluble polyoxyethylene or cellulose ether derivative containing a plasticizer. Any number of the webs may be loaded with active substance. Preferably the ' .
.., :

ll il~85Z~5 paper composition webl~ are loaded with activo substnncc.
.~
3 An alternate method for stacking the web3 which are loaded with g active ingredient is to supply them directly from the deposition apparatus.
The width of the web is usually 12 to 2i ¢m. The web, as stored on rolls 6 or supplied from the despostion apparatus, may initially be multiple7 of the final width which is dit to the final desired width as part of the 8 stacking process .
Once the web i8 ~t~cked, the continuous resultant bundle is guided 11 to a lamination station. Apparatus known in diverse arts for bringing stripR
12 of flexible films together and forming a laminate therefrom is generally appli- ;
13 cable to the practice of this embodiment of the present invention. As 14 already discussed, the ~rea of deposition of acti~re substance on the web strips or sheets will vary depending, for example, on the method of

16 sealing the lamination. The cutting and finishing of the l~minate may like-

17 wise vary m accordance~with the invention. For example, laminates can

18 be treated as in the rotary forming process described above. However, -~

19 the lamination station could also consist of a pair of reciprocating die plates which form, seal, and cut dosage forms from the continuously feeding 21 web stack. A typicnl die plate would have a surface of approximately22 25 cm x 25 cm.

24 The laminates formed in accordance with the present invention are, in a pnrticulnr embodiment, unique in that they nre scalcd only at the cdges as opposed 26 to cach shect being totally senled to the adjncent sheets. It has bcen round that, 27 unexpectedly, suitable dosagc forms can be produccd from a stack of layers of .,.. . , ~ .

1~852~35 web whercin up to six Inyers of p~p~r composition web ure interspcrsed l~etween 2 layers of u web comprised of a heat sealuble polymeric composition by the application of hent and pressure to the stuck by the cutting means durine unitizing During the unitizing operation, the layers of polymeric web in the stack become G~e ~or~ec¢~
-~by the heat and pressure und "~pread" to cover and seal the edge~ of 6 the intervening layers of psper composition. It is readily apparent that the 7 top and bottom layer~ of such a laminate must be of polymeric composition. It is 8 preferred that the medicamont in a paper-polymeric web stack be loaded to the paper layers of web. It is readily apparent from the foregoing disclosure that such a laminate sealed only at the periphery posseBses 8 superior rate o release 11 of medicament than & similar stack of webs which has been tot~lly laminated.

13 An alternative method for forming the dosages from the web ~tack is to pass:
14 the stack between rotating cylinders which have invidiual dual dies on the outer peripher~. The dosage units are formad, sealed and cut from the continuously 16 feeding web stack as it passes between such rotating cylinders.

18 Some pharmaceutical compounding benefits are realized from the use 19 of laminating techniques are herein considered. First, tlIe laminat-~ r~ w~/~h ing techniques provides b~_ facilitAte the compounding of two 21 or more-~active substnnces which are incompatible without 22 the need to resort to the Dddition of stabilizing substanccs or a spccial com-~ 52~5 , ``

pounding techniquc such as, for example, encapsulation of one or more 2 ingrcdients. Since up to, for example, 60 IRyers may be utilized to form a .~ e ~l 3 laminate, this embodiment of th~ invention is ideally ~for pharmaceu-4 tical preparations containing 8 lurge number of active substances where there are numerous possibilities of incompatibilities such as, for example, 6 multivitamin preparations. Further, the insulating effect of l~yers of a lamin-7 ate and the deposition or loading of active substance to the web in the dry state malces such techniques ideally suitable for the dispensing of effervescent preparations. In such preparations, it is appreciated that the web compos-ition would have to be such that it would resdily dissolve or disperse in 11 water. Also, as discussed ~bove, loading of the active ingredient onto the 12 web in the dry state is advanta¢eous wherein the active substance is adver-13 sely affected by moisture.

Further regarding the laminate process of the present invention, it 16 is within the scope thereof to vary the formulation of the various layers 17 within a laminate as well as to control whether each is coated with active sub-18 stance. Obviously, the surface of the top and bottom layers of a laminate 19 which will bc exposed is not coated thus providing effective internalizing of the active substance. For, example, it has been ~ound that interspers-~4 27 ,~

.. . Il,, ................. . I
" ' , ~ , 52~5 ing one or more Inyers of 4 stalch~basecl formuIDtion in ~ cellulosic l~min-.~ flte more expediently udds plasticity to the laminute than increasing the 3 quantity of plasticizer in the formulation of the cellulose layers.

S Regarding the method of forming discuæsed above, it is preferred in 6 accordance with the invention to deposit or load the web with active ingre-7 dient in the wet form wherein forming is by the convolute wind or fan-8 fold process. The rotary forming and lamination processes are equ~lly 9 amenable to deposition of active substance in wet or dry form with the choice being dependent on the characteristics of active ingredient being 11 loaded, for example, solubility in the particular solvent being utilized, 12 stability to moisture, and the like.

Unitizing ~
16 As a practical matter, unitizing cannot be discussed without ~Iso 17 discussing sealing, and without first having discussed fabrication, since, 18 by defintion, cutting or unitizing the formed webs could expose some 19 active ingredient at one or more of the outer surfaces. An exception to this would be having the loading operation adapted to deposit active 21 substance at short intervals as opposed to a continuous deposition thereby22 having active substance "spot deposited" and surrounded on all sides 23 by uncoated web. In view of considerations of manufacturing equipment 29 and the need to maintain the integrity of the deposition coating for on-line testing, it is preferred to load active substance continuously onto the web 26 in sufficient amount so thut the unitizing operution produces dosago forms27 containing a lherapeutically cffic~cious dosDge. In certuin of the operations .

I - 51 - ' . .. :. , ~:

11 10852~5 described herein, e.g. thc fan-folding proccss, thc outcr rnar~ins of the 2 web may be lcft frce of activc substunce to insure internali~ing of the active ~_~ Ms~ance~ to ` ~ 3 substance and, in certain ~ provide excess web which csn be 4 utilized to seal the unitized dosagc forms.
S ..
6 The cutting of the formed web must be accomplished in such a manner 7 so as not to deform the web. The cutting operation itself may be accomp-8 lished by stationary or rotary knife blades, by single- or two-stage dies,9 or by other conventional methods. To assure that the fabricated web will not be deformed during the cutting operation, seversl cuts may be made 11 from different angles. Also, as discussed above with regard to rotary 12 forming, the formed web can initially be crimped slightly or indented to 13 compensate for the distortion caused by the high speed unitizing operation.

The formed, loaded web may be unitized by individual separation, 16 i.e. the form~tion of one unit at a time such as by cutting exact lengths from 17 a rod or, preferably, a number of units may be formed simultaneously 18 such as by cutting a convolute wound rod into a number of dosage units 19 utilizing a number of uniformly spaced cutting edge$. Another method of forming a plurality of dosage units simultaneously would be the use of 21 shaped dies, either single or double and rotnry moulltcd, or recipro-22 cally mounted on plates to cut a laminated web or a canvolute wound rod-23 like structure. The shape of the final dosage form preferably has con-24 mctic appeal and is such that a numbcr of shapcs will fit into u die platcWit]l essentially no waste except at the periphery a recturlgle, a square 26 or, preferably, a hexagon.

S2~5 The shape of the do~aee forms pr~epared from rods can 11160 be 2 determined by the 6hape of the cutters. The cutter, for example, could 3 be of rectangular shape with the parallel lar~er sides moderately conc~ved 4 so that the ends of the dosage forms cut therewith will be slightly rounded.
Other variations will be apparent to tho~se skilled in the art. lt is to be 6 borne in mind, however, th~t such lateral support as is required to pre-7 vent wrinkling and flashing must be applied to the fabricated dosage forms 8 during the unitizing operation.

It is within the scope of the present invention to combine the uniti-11 zing and final sealing operations. Although there are numerous way~ by 12 which the dosage forms can be sealed, the most commonly combined with the 13 unitizing operation are heat and/or pressure. In addition to effecting 14 a seal on the severed edges of the dosage form by heating the cutting tool, heat and pressure can be applied through the die to bond the laminate. I
16 Also, the use of moisture or a fugitive solvent to seal the trailing edge ¦ -17 of the convolute wound rod as mentioned above can be extended to the cutt- ¦
18 ing operation by applying such solvent to the cutting surface. Heat and/or 19 pressure may also be applied at the same time to ensure a proper ~eal.

21 The methods whereby the unitizing dosage forms prepared in 22 accordance with the present invention may be sealed are not unconventional 23 to the plastics handling and laminating arts. These include, in addition 24 to the use of water or other fug~tive solvents such as, for example, ethanol, methanol and chloroform, the application of pressure and heat, the applica-2G tion Or a separatc adhesive, infrarcd heating, ultrs60nic bon~ling, encap-27 sulating or combinations of two or more Or these. A preferred method of : ,.

_53_ 1 85~g5 ¦ scnling dosa~c forms within the scope of the present invcntion is the use 2 of an overwrap which may bP preprinted if desircd. This may be, for example, 3 a thin laycr of edible polymeric mutcrial such as, hydroxymcthyl cellulose, 4 modified starch, and gelatin which is sprayed on to the dosuge units of a bath into which the dosage units arc immersed. Such layer could be seif sealing 6 such as, for example, by removal oî a fugitive solvent. More preferred 7 methods of effecting a sealing layer on the unitized dosage units in accord-8 ance with the invention are encapsulation and basket sealing.
In the first of these methods, the solid dosage units are p~ssed 11 between converging layers of flexible film of, for example, gelatin which 12 enclose the dosage form such as that illustrated in Fig. 6A. The gelatin film 13 is then heat sealed and cut to shape. Apparatus for encapsulation of liquids 14 by this method is recognized in the pharmaceutical industry snd such appara-tus can readily be adapted to coat the novel dosage forms of the present 16 invention .

18 A second method is basket sealing which may be accomplished by at 19 least the following two processes. In the first, preformed baslcets are prepared from material such as, for example, gelatin, or a cellulose derivative by 21 apparatus well known, e.g. in the art of plastic molding, i.e. injection 22 molding. The unitized dosage forms are placed automatically into these 23 baskets at high speed and the baskets are then covered by an overlayer 24 which is sealed to the basket by any of thc sealing methods alluded to herein, preferably utltrasonic welding. The baskets ure scparuted by cutting ~vith 26 ¦ a stationary or rotury cutting edge. The walls or the preformed basket are 27 ¦ usunlly thicker than the top or sealing luyer. The seuling layer, howevcr, I

52~5 is sufficiently thick to protect the dosage form yet is such that the dosage form will be released from the basket via the sealing layer within a very short time after ingestion, usually within a few seconds after reaching the stomach. Alternately, the basket may be ~ormed from identical halves which are sealed by methods such as have been described herein.
` An alternative to the basket seal described above is to form a continuous support web or strap of material such as described above for the basket and cut holes therein to exactly accommodate the dosage form, e.g. fan-folded dosage forms as illustrated in Figure 6A. In this em-; 10 bodiment, the unitized dosage forms are placed into the holes, e.g. by a pin through the hole and a second pin on top of the unitized dosage form ;
to keep it under compression. The strap is then sealed by the addition of a top and bottom layer of similar material while maintaining compression on the dosage units. The thickness of the strap is in no instance more than that of the dosage units. The strap, however, can be thinner than the dosage form but not less than approximately half the thickness thereof.
It is preferred that the support strap be close to or equal to the thick-ness of the dosage form for a number Oc reasons. First~ the sealing film can be as thin as that described above in connection with the basket since ~-;~ 20 it is not significantly distorted in the sealing operation. Second, a thick support web will be less subject to distortion during the perforat-ing and unitizing operations. Third, holes can be made closer together in a thicker strap thus allowing for a minimum of waste. Once the dosage form -~ has been placed in the support strap and sealed, the strap is again unitized ;~
~ às described herein. An advantage to both the basket and support strap con-;;~ cept described above is that there is web material on the outer surface ., ~, ~ - 55 -....
, "~
:, :

:- ~ ~ 35;~

~ which does not contuin acti~fe substance and which could be subjectcd to .! finishing operntions such as, for example, eml)ossing, beveling, and the 3 like without rislc of los~ of ~ctive substance. Also, the use of the basket 4 or the support strap concepts facilit~lte the use of varying colors in the final dosage form, e.g. by making the support web, sealin~ strips or the 6 dosage units themselves contrasting colors, an especially pleasing and dis-7 tinctive appearance may be achieved.
9 The material to be utilized in preparing the basket, center support str~p and sealing films described abovc must, as is the case with the webs them-11 selves, meet critical tests. In addition to the obvious pharmaceutical criteria 12 of purity, having good shelf life, being non-toxic and compatible with the ~3 active substance utilized, the material must have good surface quality, color 14 and ink receptivity, ~tructural inte~rity, deformability, dimensional lS sta~ility and release of flctive ingredient in water. The preferred substances 16 for this use are hydroxypropylcellulose and methylcellulose. An 17 especially preferred composition comprises hydroxypropylcellulose, 18 a starch or starch derivative as an extender and disintegrant, a plasticizer 19 such as, for ex~mple, polyethylene glycol, suitnble pigments, e.g.
titanium dioxide and an antioxidant such as, for example, BHT.

22 Quality Assurance 24 One of the major advantages realized by thc novel dosage forms of the subject invention is that they are amenablc to on-line, non-destruc-. .
26 tive quality assurance. In the contcxt of t}le prcsent invcntion thc term "non-27 destructive" is mcu1lt in the practical sense as opposcd to thc strict litcral '`. ' 11 ~ ~35f~5 definition. By this is mcant thut quality assurance of tlle novel dosage forms 2 of the invention is provided during high-specd manufacturing procedures 3 with the actual loss of substantially lesci than 1~ of the dosuge form. Since the 4 novel dosage forms of the invention can be produced with a low standard devia-tion in dosnge and therefore a manufacturing excess of less than the standard6 6 conventionally accepted in the pharmaceutical industry at the present time, 7 the very small percent of the dosage form lost during testing becomes in8 essence, zero when viewing the tolerances of the instant manufacturing process 9 in total.

11 The novel dosage forms of the present invention, as a finished product, 12 possess quality assurance of the manufacturing process, a concept unique in 13 ~ the pharmaceutical industry. The on-line testing procedures giving such 14 assurance are to be clearly distinguished from such recognized pharmaceutical quality control procedures a~ chemical and physical control of the ingredients of 16 the dosage form before the manufacturing has begun, destructive testing of 17 solid dosage forms after the manufacturing procedure has been completed both 18 for physical characteristics, e.g. dissolution rates, incidence of capping and l9 the like and chemical characteristics such as potency, presence of incompatibilities and the like and physical quality checks of solid dosage forms such as, for 21 example, rnanual inspection of bicolored capsules to assure that each has ends 22 with contrasting colors. Such tests, which are recognized and commonly . 23 practiced in the pharmuceutical industry and described in the official compendia, 24 be~r no relution to and are not suggcstive of the on-line manufucturin~ assur-ance which is a critical feature of the solid dosa~e forms of the Invention.
26 It is to bc noted, however, thut ccrtain conventionul procedures such as, ror 27 example, strict 4uality control and tcsting of ull ingredients prior to the manu-:,' . I .

~ _57_ . ~, . . . . .
.. . , , ,. : ; ~

~0852~5 facturing process form an integral part of the preparation of the dosage forms contemplated herein as is the case with any good pharmaceutical manufacturing practice.
The on-line quality assurance of manufacturing possessed by the novel dosage forms of the present invention is provided by the fact that all such forms described herein begin with a continuous edible web which can be tailored to non-destructive testing. First, the web production itself is monitored for the physical characteristics of the web to assure that the web is uniform and is free of defects. For example, the web can be made to pass through a resonant cavity where a microwave passing through the web is continuously monitored for web thickness, i.e. once the resonant frequency is established, changes therein are indicative of changes in web thickness. Other means of monitoring web thickness include ; laser beam diffraction, fluidic sensing and physical contact sensors. It is also possible in accordance with the present invention to test the web for weight per unit area and for defects. ~ ~
The preferred method of testing the web for weight per unit -area is soft x-ray absorption, e.g. a wavelength of about 4 angstroms. ~ -Beta-ray absorption unitizing a PM 1~7 source is also feasible. Web de-fects such as specks, holes and streaks can be detected by laser beam scanning. Holes in the web can be detected by the electrical discharge method utilizing equipment which is commercially available.
The methods detailed above are equally applicable in thos e in-stances where the web receives a second coating either in the form of one or a number of additional webs or a protective coating applied to a loaded ~:`
,, 52~5 . ~
`

web. Laser scanning is particularly advantageous to the on-line quality assurance of such coatings.
A second major area of quality on-line assurance in accordance with the method of the present invention is monitoring of the amount of active substance deposited onto the web and also the uniformity of the `~ coating operation. It must initia~lly be remembered that a distinct ad-vantage of the process by which the novel dosage forms of the present -invention are produced is that the active substance is loaded to the web in a form which is amenable to the testing procedures to be described ~ 10 hereinafter, i.e. in finely particulate form or as a fine film.

- There are several methods contemplated herein for analysis of :. - .
uniformity of deposition of active substance. For example, a photon counter can be utilized to measure ultraviolet absorption of the highly attenuating active substance-web system. Soft x-ray absorption utilizing a wavelength of about four Angstroms and beta-ray absorption can also be utilized. Light scattering apparatus is preferred since it is ideally suited for monitoring particle size and concentration in the powder cloud or on the web. The apparatus suitable for such operations is commercially available.
The fabrication, unitiæing and finishing steps described above are likewise amenable to on-line testing procedures such as described ~; above in connection with the web. Such tests will, of course, involve physical parameters of the web after fabrication such as dimension, thick-ness, uniformity and the like. Similar tests are also carried out on the unitized dosage forms regarding shape, uniformity and the like.
The discussion to this point has centered on means whereby the '`':
novel ':,~

. .

. '~

, ~ .
. .
,::.

5~5 dosuge units of thc invcntion llre testcd non-destructivcly on-linc during 2 production. Two a(lditional tcsts arc contcmplated within the scopc of the ~ ~h ~
.~ 3 invention and without departing from t~s spirit of the tcrminolo~y "non-4 destructivc testing".
S
6 In the first such operation, a minute portion of the web is periodically removed on-line by cutting with knives, dias, fluid jets or a laser beam.
8 It i9 comtemplated that the portion of web removed will not destroy the 9 integrity of the web or adversely affcct any of the fabrication operations.The sample of the web can be removed before or after the active substance 11 ~ is loaded thereon or, in some instances, during early stages of fabrication, 1~ e.g. when a few webs have been stacked in a preliminary laminating or folding 13 oper~tion. The sample thus removed is chemically analyzed both for web com-14 position and for activc substance. This analysis is also carried out on a quantitative basis particularly with reference to active substance.

17 In addition to the spot analysis, the finished dosage forms are sampled 18 and subjected to performance assurance on-line. While such testing is ~ procedure l9 required at present with most solid dosage forms marketed in the United States it is not carried out on-line during the manufacturing operation as 21 is the case with the present invention. First, it must be borne in mind that 22 the novel dosage forn-s of the present invention flre not encumbered by batch 23 restrictions by virtue of the process whercby they ure manufactured. A
24 "batcll" in accordance with the invention can thercfore bc thc number of dosnge units fulling between two samples which meet the pcrformancc specifications 2~ plovided that ~s~id number docs not e~;ceed thc saInpling rccluircments of 27 thc ~edcral l:ootl and l)ru~ AdministrLItioll. Sincc the sumpling proccdures : r ~ - 6n -',' ~1 ~085Z~5 contemplnte(l in flccorclnnce with thc invention substantiully exceed such require-2 mcnts, a "batch" of novcl dosa~e units claimed hcrein cun be nny convcnicnt 3 numbcr, e.g. the number of units ~uhich can be produced from a givon 4 production lot of active substance.
6 A second unique aspect of the per~ormancc assurance testing of the novel 7 dosage forms of the subject invention i9 that the results of such tests, as well 8 of those of all other on--line tests discussed herein, can be computerized and 9 utilized to adjust the parameters of the munufacturing process. By so doin~, a negative reading on any of the tests signifies the beginning of a run of 11 dosage units which must be isolated and the next following positive result 12 after corrections are made flutomatically terminates the run. The dosage 13 units produced between these two tests must then be further tested to determine 14 how many conform to specifications. Where tests are being conducted on-line on the web, e.g. on the amount of active substance deposited, a negative 16 reading can be automated to simultaneously actuate two functions. First, 17 the web can be marked with a spot of non-toxic dye thus allowing for the 18 production procedure to be temporarily halted and a section of web manually 19 removed. Second, the reading, through a computer, actuates an adjustment in the amount of active substance being loaded onto the web to either increase 21 or decrease said amount to conform to spccifications. When the web passing 22 the testing unit again conforms to spccifications, a second spot will automati-23 cally be made on the web thus marlcing the length of web not meeting specifi- ;.
24 cations. Similar operations are established at each of the on-line test sites.
`- 25 26 Regarding the performanc¢ analysis operation, rDndom samples of finished 27 dosuge units are removed nnd automatically depositcd in aliquots of tcst .:'' ~' . .

_61_ , .

~ 15~5 solution and tested for dissolution rate. The particulur criteriu utilized to test for dissolution of the unit dosnge forms will vary with the uctive sub-3 stance or substnnces present therein. For example, a sample dosage 4 unit can be added to a suitable solvent thereby forming a solution of the activ~
ingredient . The resulting test solution can be photometrically scanned to 6 record the concentration of active ingredient as a function of time after the 7 test Wlit was inserted therein. Other possible indicators which could be 8 measured in the test solution are changes in pH, color, heat, chemical reaction 9 and the like. I~leans whereby each of these changes can be ~utomatically recorded as a func~ion of time are within the skill of the ~rt. Once the dissolu-11 ` tion information is recorded, it can be utilized by a system such as a computer 12 to make such adjustments in the formation, unitizing, finishing and sealing 13 operations as are required to correct or improve the readings.

The on-line testing procedures described herein are in all instances 16 amenable to testing of the entire web, e.g. a device which tests for web 17 thickness. However, in certain instances testing of the entire web may not 18 be feasible from the standpoint of economics. For example, it is possible 19 to test a small area of web using a light scuttéring sensor and further possible to mount two or more sensing devices in close proximity to scan a corresponding number of small widths within a passing web. The cost 22 of equipment required to have the total wcb scunned may, however, be 23 prohibitive. Thereforc,where only limited areas of the web can be checked, 24 thc testing equiE)ment can bc mounted on means which facilitate its oscillnting ucross the width of the web. The percentage of web alld 26 thercfore finiYhe(l dosage unils tested in this manncr fur cxceeds uny non-27 destructivc tcsting procedures presently carried out in thc pharmaceutical .

-~2-lOB52~35 industry .
~.~
3 Finishinc and rrinting S As discussed at v~rious points herein, the finishing operations for 6 the novel dosage forms of the present invention may be conducted independently 7 or, preferably, in combination with other operations, e . g . unitizing .
8 ~inishing in terms of the novel dosage forms of the present invention is 9 divisible into two basic considerations, i.e. the uniformity of the surface s of the dosuge form and the finish or appearance of the surface thereof.
11 . . ; ' ' 12 Uniformity of surface of the dosage forms of the invcntiorl may or may not be a problem depending on the technique employed to unitize the dosage 14 forms from the continuous stack and whether ~ sealing operation is performed.
For example, wherein a laminated stack of webs is cut to a particular shspe 16 as described above, a small flaslling may be evident where thc cutting means 17 meet. Also, there may be some end or side flashing from the unitizing ;
18 operation in dosage forms formed by other preferred methods of fabrication.
19 Generully, however, the fabrication techniclues of the present invention ~ .
minimize the incidence of such flashing.
21 '`
22 Flashing as described herein is generally removable by mild abrasion :
23 such as, for example, by subjccting the dosage units to mild tumbling action 24 ~ or without the presence of a mild abrasive substance such as salt crystals.
It is realized that such action must, in most instunccs. p rccede printing 2G operations.

:~ . , . .

Il ' ~ ........... . I

l ~ l ~
~ 52~5 The :;urfucc uppcnruncc, i.c. thc gloss of the dosn6c forms of thc prcsent '.? invclltion mny vary from n mildly buffcd uppcarnncc to rcnsonably hi~h 61oss 3 depending on the tcchnique utilizcd ~ncl the finish dcsircd. Wheroin ~ealing 4 techniqures such us, for exsmple, the basket scaling or cncapsulation mcthods referred to above are utilized, the glos~ of the finished surfnce can be 6 adjusted as desired by merely the selection of material utilized in forming 7 the seal. The same is true wherein an overwrap is utilized to seal the dosage forms 8 Wherein such sealing operations are employed, complete removal of the flashing is 9 usually not required since the overwrap assures completo continuity of surface.

11 The printing operation is likewise dependent on the fabrication and 12 sealing techniques utilized; Printing may be effected on the web itself 13 at any convenient point in the overall manufacturing operation. For example, 14 tlle outer layer of a laminated dosage form may be printed prior to the fabrication operation, as part of the unitizing operation, or even after unitizing i~
16 completed. Dosage forms prepared by, e.g. convolute winding, can be printed 17 while still in the continuous rod or stack. Wherein the dosage forms of the inven-18 tion are sealed by the application of an overwrap, printing is preferably carried 19 out after the overwrap is applied although it is within the scope of the invention to print on the dosage form und apply a clear overwrap therafter. The printing of solid unit dosag~e forms prior to completion of compounding thereof as is comtem-22 plaled herein is a concept unique in the pharmaceutical industry.

24 The selection of a printing method is dependent on a variety of factors thc most important of which is the physical nature of the substrate to be 26 printed. The ~elcction of an appropriate method is likewisc rclutive, to a 27 dc~ree, to thc point in the overall n~anuf~cturing operation wher~ printing is curricd out, i.e. whcthcr thc wcb would bc l)rintcd prior to fubrication, :~

the finished dosu~c forms would be prinlcd or printing would be curried out 2 at somc intcrmedinte point, perhaps in combinatioll with other operrItions 3 such as, for example, uniti~ing. The printing method and apparatus inherent 4 thereto can be selected from the following: offset and direct Ictterprcss; offset gruvure; lithograph; electrostatic powder gravurei electrostatic screen stencil;6 ink jet and the like. Of these, offset gravure is the method of choice although 7 other methods may be utilized in particulur instances and new methods of8 printing as come to hflnd and are adaptahle to the technology described herein g are considered to be within the scopc of the invention.

11 It will be readily appsrent from ~he foregoing discussion of finishing 12 and printing operations that there are a number of ways in which the color 1~ of the novel dosage forms of the present invention can be varied both in hue 14 and intensity. First, the web composition itself can contain a color which can build in intensity us layers of web are joined during the various fabrication .
16 operations. The color may also be imparted by an overwrap or sealing layer.
17 Wherein the basket or encapsulation me~hods of sealing are utilized, two or 18 more contrasting colors may be possible by the obvious expedient of varying 19 the color of the various sections thereof. The dosage forms prepared by lamina-tion are also amenable to variations in color simply by varying the color of 21 the webs fed into the laminating apparatus. Other variations of these ~echniques 22 will bc readily spparent to those skilled in the art.

24 Active Ingrcdicnt 26 The novcl dosage forms of the present inv~tnion are, us Q practical 27 matter, unrcstrictcd in terms of the type of activc substanco for which they . . .

, . , ~

5Z~

cun servc as a vchicle. rhc terms "activc sllbstunce", "nctivc ingrcdient"
2 and "mcdicamcnt" which are considered to bc synonymous in the contcxt 3 of the aubject invention and sre utilized interchangeably throughout the 4 instant specificntion and claims can l)c defined as any substance which will produce a pharmacologic response in the body. Such substances include 6 but are by no means intended to be restricted to the following:

8 The benzodiazepines such as, for example, chlordiazepoxide, dia-9 zepam, flurazepam, oxazepam, chlorozepate and the like. Additional compounds falling under the heading 'tbenzodiazepines" are described in 11 ` "The Benzodiazepines" Garsttini, Mussini and Randal, Raven Press 1973 12 the disclosure of which is not intended as a limitation on the term;
13 `

Other tranquilizing agent~ such as, for example, reserpine, thio-propazate and phenothiazine compounds such as perphenazine, chlorpro-16 mazine and the like;

18 Sedatives and hypnotics such as the phenobarbitals, methylprylon ;~
19 glutethimide, ethchlorvynol, methaqualone and the like;
.
21 Psychic encrgizers such as, for example, amitriptyline, imipramine, ~ :~
22 methylphenidate and the like; ~,~

24 Nnrcotic and non-narcotic analgesics such ns codeine, levorphanol, morphinc, propoxyphene, pentazocine and thc likei 26 ~nalgcsic - antipyrctics such as, for examplc, aspirin, phenacctin, ll .' , 1.
- OG -~1 1013~Z95 salicylumide and thc like;

3 Anti-intl~mmatories such as, ~or exumple, hydrocortisone, dexa-4 methazone, prednisolone, indomethacin, phenylbutazone and the like;

6 Antispasmodics/unticholinergics such as, for exa;nple, atropine, papaverine, propantheline, dicyclomine, clindinium and the like;

Antihistamine/antiallergenics such as, for example, diphenhydramine, 11 ~ ¦ chlorphenir ine, tripelenn~mine, brompheniramine and the iike;
12 Decongestants such as, for example, phenylephrine, pseudoephedrine ~4 and the like;

Diuretics such as chlorothiazide, hydrochlorothiazide, numethiazide, ~ :
16 triamterene, spironolactone and the like;

18 Nutritional substances such as, for ex~nple, vitamins, ~essential amino acids and the like; .
21 Anti-Parkinsonism agents such as, for example, L-DOPA alone and in 22 combination with potentiators such as N -DL-Seryl-N -(2,3,4-trihydroxy-24 ~ ~ benzyl) hy ::zine;
Androgenic steroids SUC}I as, for examl)le, methyltestos~erone and 26 fluoxyme&terone; .
27 . .

: ~ ~

~0852~5 Progcstationul a~ents such ~s, for example, pro~,testoronc, cthistcrone, ,t norcthynodrel, norethindronc, medroxyprogesterone and the like;
4 Estrogens such as, for exumple, estrone, ethinyl estradiol, diethyl ~tilbestrol snd the like;
7 Hormonal preparations such as, for example, the prostaglandins, 8 ACTH and the like;
Antibiotic/anti-infectives such as, for example ~ the penicillins, : ~ ~ra~ e/,~e cephalophorins, tctrncy~ine, chlortetracycline, streptomycin, erythromycin, 12 sulfonamides such as sulfisoxazole, sulfadimethoxine, sulfamethoxazole 13 and other agents such as nitrofurazone, metronidazole and the like;
, 14 Cardiovascular agents such as, for example, nitroglycerin, pentaery-thritol tetranitrate, isosorbid dinitrate, digitalis preparntions, e.g. digo-17 xin and the like;

19 Antacids/antiflAtulents such, for example, aluminum hydroxide, magnesiwn carbonato, simelthicone and the like;

22 Other therupeutic agents and/or combinutions of agents such as are 23 recognized in the medical arts us being therupeuticall~ useful .

The active substanccs us utilized in the subject invention may be in the 26 frce ~orm or in uny non-toxic pharmnceuticully ucccptul)le form whercin thcir 27 thcrupcutic activity is retnined. For cxample, acidic substallces may be present ,, ~

2~5 ns cstcrs o~ us sults with ph~rmnccuticnlly llcccl)tllblc inorgullic bascs such us 2 for cxample, the sodium snlt, thc potussium snlt und tllc likc or orgnnic bascs such 3 as amines or quatcrnary forms. Basic substanccs may be present us salts with 4 orgunic acids such as the acetate, th~ turtrntc nnd the like. Certain substances such as, for example, ampicillin mDy be present in a hydrated form. In general, 6 sny pharmaceutically equivalent form of a given activc sulbstance which is recog-7 nized in the pharmaceutical compounding arts for said substance is utilizabl2 in 8 the dosnge forms of the present invention subject, of course, to the limitation of 9 incompatibility with the web substrate. In those few instances where such incom-putibilities m~y exist, they are readily ascertained by simple experimentation.
~. 11 ~ :
12 The amount of the active substance or combination of substances to 13 be incorporated into the novel dosage forms of the subject invention is usu~lly 14 that amount recognized as being an effective therapeutic dosage for the parti-cular medicament. In general, the amount of active ingredient present in a 16 single dosage form should not exceed about 500 mg with ~ practical upper limit 17 being about 750 mg.

19 Dissolution 2û
21 As stated herein, the novel dosago ~orms of the present invention possess 22 an extremely consistcnt rate of relcase which is also controll~ble to meet 23 desired specifications. Therefore, whatever pattern of release is contemplatcd, 24 the dosugc forms of the subjcct invention exhibit u consistency of ratc of rclensc within such pattern which is superior to thut exhi\~itcd by convcntional26 solid dosu~e forms, e.g. tablets and cupsulcs.

28 I;ig. 7 grul)hicully illustratcs thc superjori~y in r clc~sc ratc of the dos~ge -6~-~1 .

rorm.s Or the invention in comparisotl with a conventiollul soli(l oral dosuge form, .~ i.e. commerciul cnpaulcs. ln thc experimcnt illustratcd in Fig. 7, six randomly 3 sumplcd conventional capsules each containi~ a like amount of the same 4 active in~redient wcre each placed in 100 ml . of Artificial Castric Fluid, U.S.P. (without enzyme) . The fluid was maintained with stirring st 37C.
6 The fluid in each of the reaction flasks was constantly flitered and circulated 7 through flow cells in an nppropriste spectrophotometer.
. 8 9 The absorbance of the fluids was read st one minute intervals and the precent of active ingredient dissolved calculated for each reading.
. In Fig. 7 the f~stest and slowest dissolving semple of each group are shown and 12 the shaded srea between covers the remaining four samples. Viewing Fig. 7, 13 two conclusions sre resdily reached. First, the novel dosage forms of the 14 subject invcntion clissolve much more r~pidly than the conventional capusles tested. Second, the variation among six samples of the dosage units of the 16 invention l,vas strikingly less than of the conventional capsules tested.
-~ These results clearly demonstrste the superior consistency of release which is 18 chsrscteristic of the dos~ge forms of the present invention.
19 .
'rhe blood level curves depicted in Fig, 8 also compare the novel dossge 21 forms of the subject invention with commercially availnble capsules containing 22 the same smount of the ssme active ingredient. The b]ood level curves sre 23 theorcticully drawn based on two rates of input into fl or.e-compartment 24 pharlllacokinctic model. The l)loocl level curvcs nre buscd on a theoretical 100~6 sbsorption of the amount of active ingredicnt rclcuscd from the dosage 26 form at a point in time and so ~e proportionnl to thc dissolution ratc.
27 The differcncc in blood level curves is thercfore a fullction of dissolution ratcs.
. .

~ -'10- ~ ' It is cleurly cvidcnt rrom thc data ilJustrutr~d l-ig. 8 tIIat the dosagc forms 2 Or ~he subjcct invention not only rcuch etfective blood levels more r apidly3 but attaill u higher blood level of active ingredicnt than the convcntional 4 capsules. The ability to attain a higher blood Icvel Or active ingredient more rapidly is a distinct advantage purticularly in the administration of .
; certain types of chemotherapeutic agents, e.g. antiobiotics, cardiac active agents and the like.

' 11 ` 12 1~

19 1.,' 2fi 27 ., :~

~71~

Claims (73)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A solid pharmaceutical unit dosage form comprising a plurality of layers of an edible, therapeutically inert web of a polymeric or paper type, at least one of said layers having a composition comprising one or more medicaments uniformly loaded in finely particulate form to one or more surfaces, said layers of web being arranged so as to have substantially no medicament loaded to an outer surface thereof, said layered arrangement of web being sealed so as to completely internalize said medicament.

2. A unit dosage form according to claim 1, wherein said web of a polymeric composition comprises an organic film forming ingredient and one or more plasticizers.

3. A unit dosage form according to claim 2, wherein said polymeric composition comprises additional modifiers.

4. A unit dosage form according to claim 2, wherein natural or chemically modified starches or dextrins, proteins, cellulose derivatives, polysaccharides or synthetics are used as organic film forming ingredient.

5. A unit dosage form according to claim 4, wherein gelatine is used as protein.

6. A unit dosage form according to claim 4, wherein sodium carboxymethylcellulose, hydroxypropylmethylcellulose or hydroxyethylcellulose is used as cellulose derivatives.

7. A unit dosage form according to claim 4, wherein pectin, acacia, xanthin gum, guar gum or algin is used as poly-saccharide.

8. A unit dosage form according to claim 2, wherein the amount of film forming ingredient is from 5 to 95%.

9. A unit dosage form according to claim 8, wherein the amount of film forming ingredient is from 40 to 90%.

10. A unit dosage form according to claim 2, wherein glycerin, polysorbates or mixtures of mixed mono- and di-glycerides of saturated fatty acids are used as plasticizers.

11. A unit dosage form according to claim 10, wherein the amount of plasticizers is from 1 to 60%.

12. A unit dosage form according to claim 11, wherein the amount of plasticizers is from 10 to 50%.

13. A unit dosage form according to claim 3, wherein disintegrants, fillers and extenders are used as modifiers.

14. A unit dosage form according to claim 13, wherein various types of starches, casein or gelatine are used as dis-integrants.

15. A unit dosage form according to claim 14, wherein the amount of disintegrant is up to 40%.

16. A unit dosage form according to claim 15, wherein the amount of disintegrant is from 5 to 20%.

17. A unit dosage form according to claim 13, wherein titanium dioxide, chalk, kaolin, mycrocrystalline cellulose or calcium carbonate are used as fillers or extenders.

18. A unit dosage form according to claim 1, wherein said paper composition comprises one or more fibrous materials and one or more non-fibrous modifiers.

19. A unit dosage form according to claim 18, wherein said paper composition comprises (a) from about 70% by weight to about 99% by weight of an edible fiber;
(b) from about 1% by weight to about 30% by weight of an edible disintegrant selected from the group consisting of sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-cellulose, polyvinylpyrrolidone and guar gum;
(c) from about 0% by weight to about 5% by weight of an edible surfactant.

20. A unit dosage form according to claim 19, wherein said ingredient (a) is present in an amount of from about 90%
by weight to about 96% by weight, said ingredient (b) is present in an amount of about 4% by weight to about 10% by weight and said ingredient (c) is present in an amount of from about 0% by weight to about 2% by weight.

21. A unit dosage form according to claim 19, wherein said ingredient (a) is comprised of edible hardwood fibers, edible softwood fibers or mixtures thereof.

22. A unit dosage form according to claim 19, wherein said ingredient (b) is sodium carboxymethylcellulose.

23. A unit dosage form according to claim 19, wherein in the paper composition said ingredient (c) is selected from the group consisting of polysorbate 80, sodium lauryl sulfate and dioctyl sodium sulfosuccinate.

24. A unit dosage form according to claim 19, wherein said paper composition additionally contains one or more edible, non-fibrous modifiers selected from the group consisting of edible fillers, extenders, opacifiers, electrolytes and preservatives.

25. A unit dosage form in accordance with claim 1, wherein said medicament is a benzodiazepine.

26. A unit dosage form in accordance with claim 25, wherein said benzodiazepine is chlordiazepoxide.

27. A unit dosage form in accordance with claim 1, wherein said medicament is digoxin.

28. A unit dosage form according to any one of claims 1 to 3, wherein said layered arrangement of web is a laminate.

29. A unit dosage form according to any one of claims 1 to 3, wherein said layered arrangement of web is a wound roll.

30. A unit dosage form according to any one of claims 1 to 3, wherein said layered arrangement of web is a fan-folded arrangement.

31. A unit dosage form according to claim 1, wherein the layers of web are arranged in a stack.

32. A unit dosage form according to claim 31, wherein at least two layers in said stack of webs consist of a heat sealable polymeric composition comprising an organic film-forming ingred-ient and a plasticizer therefor and at least one layer in said stack of webs consists of a paper composition comprising one or more fibrous materials and at least one non-fibrous modifier therefor, the top and bottom layers of said stack being polymeric with the proviso that there be no more than six of said paper composition webs interspersed between each pair of said polymer composition webs in said stack.

33. A unit dosage form according to claim 32, wherein said non-fibrous modifier in said paper composition comprises an organ-ic film-forming ingredient.

34. A unit dosage form according to claim 33, wherein said film-forming ingredient in said polymeric composition and said paper composition is selected from the group consisting of hydroxypropylcellulose and sodium carboxymethylcellulose.

35. A method of preparing solid pharmaceutical unit dosage forms comprising uniformly loading one or more medicaments in finely particulate form to a therapeutically inert, edible web of a polymeric or paper type, fabricating a single sheet of said loaded web into a solid geometric form of predetermined shape having said medicament substantially internalized, said form being divisible into a plurality of unit dosage forms, unitizing said geometric form into said plurality of unit dosage forms and seal-ing said unit dosage forms to completely internalize said medica-ment, said procedures including at least one non-destructive testing operation to assure uniform quality of said unit dosage forms.

36. A method in accordance with claim 35, wherein said method is carried out in a substantially continuous manner by way of automated apparatus.

37. A method in accordance with claim 36, wherein said medicament is loaded to said web in dry form.

38. A method in accordance with claim 37, wherein said medicament is uniformly admixed with a therapeutically inert, edible glidant material.

39. A method in accordance with claim 35, wherein said medicament is loaded to said web by powder cloud electrostatic deposition.

40. A method in accordance with claim 36, wherein said medicament is loaded to said web by applying a solution or dis-persion of said medicament in a suitable liquid and thereafter removing said liquid.

41. A method in accordance with claim 40, wherein medica-ment containing solution or dispersion is applied to the web by electrostatic jet spray deposition.

42. A method in accordance with claim 36, wherein said non-destructive testing operation comprises monitoring the particle size and concentration of medicament on the loaded web by way of light scattering techniques.

43. A method in accordance with claim 35, wherein said fabrication procedure comprises cutting said loaded web trans-versely to form substantially uniform lengths of loaded web each divisible into a plurality of unit dosage forms, corrugating each length of web to form same into a loosely wound coil, convolute winding said loose coils to form a substantially solid rod and cutting said rod traversely to form a plurality of unit dosage forms.

44. A method according to claim 43, wherein a web is used having a composition that is amenable to being watersealed and wherein the rods are sealed by contacting the coils with a suf-ficient amount of water as a fine spray to dampen them and sub-sequently drying the rods.

45. A method according to claim 44, wherein the applica-tion of water is limited to the point on the surface of said rod wherein the seal is required.

46. A method according to claim 35, which comprises form-ing a stack of said webs at least one of which has medicament loaded thereto, cutting said stack to unitize same into unit dosage forms and simultaneously sealing only the edges of said unit dosage forms by applying heat and pressure during said cut-ting procedure, thereby completely internalizing said medicament, said procedure including at least one non-destructive testing operation to assure uniform quality of said unit dosage forms.

47. A method in accordance with claim 46, wherein said stack of webs comprises at least two layers of web consisting of a heat sealable polymeric composition comprising an organic film-forming ingredient and a plasticizer therefor and at least one layer of a paper composition comprising one or more fibrous materials and at least one non-fibrous modifier therefor, the top and bottom layers of said stack being polymeric with the proviso that there be no more than six of said paper composition webs interspersed between each pair of said polymer composition webs in said stack and said heat and pressure applied to said stack of webs during said cutting operation is sufficient to cause said polymeric webs to deform and seal the edges of any intervening layers of paper composition webs.

48. A method according to claim 35, which comprises form-ing a continuous stack of a plurality of layers of web and sub-jecting said stack to pressure to densify and shape same into a continuous rod-like first geometric form, unitizing said geo-metric form into said plurality of unit dosage forms and sealing said unit dosage forms to completely internalize said medicament, said procedures including at least one non-destructive testing operation to assure uniform quality of said unit dosage forms.

49. A method in accordance with claim 48, wherein said unitizing step comprises uniformly transversely indenting said rod-like first geometric form and thereafter severing said geo-metric form at said indentations to form dosage units.

50. A method in accordance with claim 48, wherein said unitizing step comprises longitudinally cutting said rod-like first geometric form to yield a plurality of continuous geometric forms each divisible into a multiplicity of dosage units and thereafter transversely cutting each of said plurality of contin-uous geometric forms at uniform intervals to form individual dosage units.

51. A method in accordance with claim 48, wherein said unitizing step comprises transversely cutting said rod-like first geometric form at uniform intervals to yield a plurality of geo-metric forms each divisible into a plurality of dosage units and thereafter longitudinally cutting said forms to form individual dosage units.

52. A method in accordance with claim 48, wherein said continuous stack of a plurality of layers of web is formed by laminating a plurality of webs arranged to have the top and bottom surface free of medicament.

53. A method according to claim 35 for forming edible webs suitable for the production of solid pharmaceutical unit dosage forms comprising forming a paper web from a first composition comprising from about 70% by weight to about 99% by weight of an edible fiber in a suitable fugitive liquid and, prior to removing said liquid, adding to said web a second composition comprising a solution of from about 1% by weight to about 30% by weight of an edible disintegrant selected from the group consisting of sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinyl-pyrrolidone and guar gum and from about 0% by weight to about 5%
by weight of an edible surfactant in a suitable liquid and there-after removing said liquids, said percents by weight being of the finished web composition.

54. A method in accordance with claim 53, wherein said first composition comprises from about 90% by weight to about 96% by weight of said fiber and said second composition comprises a solution of from about 4% by weight to about 10% by weight of said edible disintegrant and from about 0% by weight to about 2%
by weight of said edible surfactant.

55. A method in accordance with claim 53, wherein the liquids in said first and said second compositions are the same.

56. A method according to claim 35, wherein said fabric-ation procedure comprises fan-folding a continuous web structure comprising at least one pair of layers of web having medicament loaded to the facing surfaces thereof and subjecting said stack to pressure to densify and shape same into a continuous rod-like geometric form.

57. A method in accordance with claim 56, wherein said unit dosage forms are sealed and unitized by:
(a) placing them in perforations of cooperating shape within an endless web strap comprised of therapeutically inert, edible material;
(b) placing said web strap between two endless webs comprised of therapeutically inert, edible material and sealing said webs to said unit dosage form-containing strap thereby form-ing a sandwich structure completely internalizing said unit dosage forms; and (c) transversely cutting said sandwich structure be-tween said perforations of said perforated strap such that ex-posure of any part of said unit dosage forms is avoided.

58. A method in accordance with claim 57, wherein said strap has a thickness equal to or greater than x and not greater than y wherein x is approximately one half of the thickness of said unit dosage forms and y is approximately the thickness of said unit dosage forms.

59. A method in accordance with claim 56, wherein said unit dosage forms are sealed and unitized by:
(a) placing them in perforations of cooperating shape within an endless web strap comprised of therapeutically inert, edible material, which endless perforated strap is secured initially to a first endless unperforated web comprised of therapeutically inert, edible material of comparable dimensions to said perforated web strap so as to form said perforations into bottomed receptacles for receiving said unit dosage forms;
(b) covering the open portion of said receptacles with a portion of a second endless unperforated web comprised of therapeutically inert, edible material;
(c) sealing said second web to said receptacles there-by completely internalizing said unit dosage forms; and (d) transversely cutting said sealed strap between said perforations such that exposure of any part of said unit dosage forms is avoided.

60. A method according to claim 35, wherein said method further includes printing of appropriate indicia on said unit dosage forms, wherein said printing is carried out during said fabricating, unitizing or sealing processes.

61. A method in accordance with claim 60, wherein said printing is carried out on said webs prior to said loading of medicaments thereto.

62. A method in accordance with claim 60, wherein said printing is carried out simultaneously with said unitizing procedure.

63. A method in accordance with claim 60, wherein said printing is carried out simultaneously with said sealing proced-ure.

64. A method according to claim 35, wherein said on-line non-destructive testing operation comprises evaluating and quantifying the uncoated web for physical integrity.

65. A method in accordance with claim 64, said evaluating and quantifying includes impinging monochromatic light energy onto the web and photodetecting said energy recovered from the web in a transmissive mode.

66. A method in accordance with claim 64, said evaluating and quantifying includes impinging monochromatic light energy onto the web and photodetecting said energy recovered from the web in a reflective mode.

67. A method in accordance with claim 66, wherein said impinging energy is electronically steered across the web.

68. A method in accordance with claim 64, wherein said evaluation and quantifying includes providing an electrical out-put for counting the number of defects and determining their size and distribution on the web.

69. A method in accordance with claim 67, wherein said evaluating and quantifying includes providing high speed parallel array inspection transverse to the relative direction of movement of the web.

70. A method according to claim 35, wherein said on-line non-destructive testing operation comprises measuring the mass thickness of said web prior to and after the loading of said medicament by determining the absorption of beta-rays or x-rays passing through the web.

71. A method in accordance with claim 70, wherein said determination of absorption occurs after said medicament is load-ed to said web and includes directing through the loaded web low energy x-rays peaked to match the absorption edge of atoms con-tained in the medicament.

72. A method in accordance with claim 71, wherein said medicament is loaded to said web as a solution or dispersion in a suitable liquid which liquid is subsequently removed and wherein said determination of absorption occurs before or after the re-moval of said liquid.

73. A method according to claim 35, wherein said on-line non-destructive testing operation comprises determining the con-centration of the medicament loaded to said web by molecular fluorescence or x-ray fluorescence.